Organosulfur inhibitors of tyrosine phosphatases

ABSTRACT

Organosulfur modulators of tyrosine phosphatases and their use in the treatment of disease are disclosed.

TECHNICAL FIELD

The present invention is directed to inhibiting the activity of tyrosinephosphatases that regulate signal transduction, and, more particularly,to the use of organosulfur compositions as tyrosine phosphataseinhibitors for the treatment of diseases which respond to phosphataseinhibition.

BACKGROUND OF THE INVENTION

Cellular signal transduction is a fundamental mechanism whereby externalstimuli that regulate cellular processes are relayed to the interior ofcells. The biochemical pathways through which signals are transmittedwithin cells comprise a circuitry of directly or functionally connectedinteractive proteins. One of the key biochemical mechanisms of signaltransduction involves the reversible phosphorylation of tyrosineresidues on proteins. The phosphorylation state of a protein may affectits conformation and/or enzymatic activity as well as its cellularlocation. The phosphorylation state of a protein is modified through thereciprocal actions of protein tyrosine kinases (PTKs) and proteintyrosine phosphatases (TPs) at various specific tyrosine residues.

A common mechanism by which receptors regulate cell function is throughan inducible tyrosine kinase activity which is either endogenous to thereceptor or is imparted by other proteins that become associated withthe receptor (Damell et al., 1994, Science 264:1415-1421; Heldin, 1995,Cell 80:213-223; Pawson, 1995, Nature 373:573-580).

Protein tyrosine kinases comprise a large family of transmembranereceptor and intracellular enzymes with multiple functional domains(Taylor et al., 1992 Ann. Rev. Cell Biol. 8:429-62). The binding ofligand allosterically transduces a signal across the cell membrane wherethe cytoplasmic portion of the PTKs initiates a cascade of molecularinteractions that disseminate the signal throughout the cell and intothe nucleus. Many receptor protein tyrosine kinase (RPTKs), such asepidermal growth factor receptor (EGFR) and platelet-derived growthfactor receptor (PDGFR) undergo oligomerization upon ligand binding, andthe receptors self-phosphorylate (via autophosphorylation ortransphosphorylation) on specific tyrosine residues in the cytoplasmicportions of the receptor (Schlessinger and Ullrich, 1992, Neuron,9:383-91, Heldin, 1995, Cell 80:213-223). Cytoplasmic protein tyrosinekinases (CPTKs), such as Janus kinases (e.g., JAK1, JAK2, TYK2) and Srckinases (e.g., src, ick, fyn), are associated with receptors forcytokines (e.g., IL-2, IL-3, IL-6, erythropoietin) and interferons, andantigen receptors. These receptors also undergo oligomerization and havetyrosine residues that become phosphorylated during activation, but thereceptor polypeptides themselves do not possess kinase activity.

Like the PTKs, the protein tyrosine phosphatases (PTJs) comprise afamily of transmembrane and cytoplasmic enzymes, possessing at least anapproximately 230 amino acid catalytic domain containing a highlyconserved active site with the consensus motif >I/VIHCXAGXXR>S/TIG. Thesubstrates of PTPs may be PTKs which possess phosphotyrosine residues orthe substrates of PTKs (Hunter, 1989, Cell 58:1013-16; Fischer et al.,1991, Science 253:401-6; Saito & Streuli, 1991, Cell Growth andDifferentiation 2:59-65; Pot and Dixon, 1992, Biochemn. Biophys. Acta1136:35-43).

Transmembrane or receptor-like PTPs (RPTPs) possess an extracellulardomain, a single transmembrane domain, and one or two catalytic domainsfollowed by a short cytoplasmic tail. The extracellular domains of theseRPTPs are highly divergent, with small glycosylated segments (e.g.,RPTPα, RPTPε), tandem repeats of immunoglobulin-like and/or fibronectintype Im domains (e.g., LAR) or carbonic anhydrase like domains (e.g.,RPTPγ, RPTPβ). These extracellular features might suggest that theseRPTPs function as a receptor on the cell surface, and their enzymaticactivity might be modulated by ligands. Intracellular or cytoplasmicPTPs (CPTPs), such as PTP1C, PTP1D, typically contain a single catalyticdomain flanked by several types of modular conserved domains. Forexample, PTP1C, a hemopoietic cell CPTP is characterized by twoSrc-homology homology 2 (SH2) domains that recognize short peptidemotifs bearing phosphotyrosine (pTyr).

In general, these modular conserved domains influence the intracellularlocalization of the protein. SH2-containing proteins are able to bindpTyr sites in activated receptors and cytoplasmic phosphoproteins.Another conserved domain known as SH3 binds to proteins withproline-rich regions. A third type known as pleckstrin-homology (PH)domain has also been identified. These modular domains have been foundin both CPTKs and CPTPs as well as in non-catalytic adapter molecules,such as Grbs (Growth factor Receptor Bound), which mediateprotein-protein interactions between components of the signaltransduction pathway (Skoliik et al., 1991, Cell 65:83-90; Pawson, 1995,Nature 373:573-580).

Multiprotein signaling complexes comprising receptor subunits, kinases,phosphatases and adapter molecules are assembled in subcellularcompartments through the specific and dynamic interactions between thesedomains with their binding motifs. Such signaling complexes integratethe extracellular signal from the ligand-bound receptor and relay thesignal to other downstream signaling proteins or complexes in otherlocations inside the cell or in the nucleus (Koch et al., 1991, Science252:668-674; Pawson, 1994, Nature 373:573-580; Mauro et al., 1994,Trends Biochem Sci 19:151-155; Cohen et al., 1995, Cell 80:237-248).

The levels of tyrosine phosphorylation required for normal cell growthand differentiation at any time are achieved through the coordinatedaction of PTKs and PTPS. Depending on the cellular context, these twotypes of enzymes may either antagonize or cooperate with each otherduring signal transduction. An imbalance between these enzymes mayimpair normal cell functions leading to metabolic disorders and cellulartransformation.

For example, insulin binding to the insulin receptor, which is a PTK,triggers a variety of metabolic and growth promoting effects such asglucose transport, biosynthesis of glycogen and fats, DNA synthesis,cell division and differentiation. Diabetes mellitus, which ischaracterized by insufficient or a lack of insulin signal transduction,can be caused by any abnormality at any step along the insulin signalingpathway (Olefsky, 1988, in “Cecil Textbook of Medicine,” 18th Ed.,2:1360-81).

It is also well known, for example, that the overexpression of PTKs,such as HER2, can play a decisive role in the development of cancer(Slamon et al., 1987, Science 235:77-82) and that antibodies capable ofblocking the activity of this enzyme can abrogate tumor growth (Drebinet al., 1988, Oncogenze 2:387-394). Blocking the signal transductioncapability of tyrosine kinases such as Flk-1 and the PDGF receptor havebeen shown to block tumor growth in animal models (Millauer et al.,1994, Nature 367:577; Ueno et al., Science 252:844-848).

Relatively less is known with respect to the direct role of tyrosinephosphatases in signal transduction; PTPs may play a role in humandiseases. For example, ectopic expression of RPTPa produces atransformed phenotype in embryonic fibroblasts (Zheng et al., Nature359:336-339), and overexpression of RPTPA in embryonal carcinoma cellscauses the cells to differentiate into a cell type with neuronalphenotype (den Hertog et al., EMBO J. 12:3789-3798). The gene for humanRPTPγ has been localized to chromosome 3p21 which is a segmentfrequently altered in renal and small lung carcinoma. Mutations mayoccur in the extracellular segment of RPTPγ which result in RPTPs thatno longer respond to external signals (LaForgia et al., Wary et al.,1993, Cancer Res 52:478-482). Mutations in the gene encoding PTP1C (alsoknown as HCP, SHP) are the cause of the motheaten phenotype in micewhich suffer severe immunodeficiency, and systemic autoinmmune diseaseaccompanied by hyperproliferation of macrophages (Schultz et al., 1993,Cell 73:1445-1454). PTP1D (also known as Syp or PTP2C) has been shown tobind through SH2 domains to sites of phosphorylation in PDGFR, EGFR andinsulin receptor substrate 1 (IRS-1). Reducing the activity of PTP1D bymicroinjection of anti-PTP1D antibody has been shown to block insulin orEGF-induced mitogenesis (ciao et al., 1994, J Biol Chem269:21244-21248).

DISCLOSURE OF THE INVENTION

The present invention provides methods and compositions for themodulation of tyrosine phosphatase activity. Such compositions andmethods will find use in the treatment of diseases caused bydysfunctional signal transduction.

In one aspect the present invention provides a method for inhibitingprotein tyrosine phosphatase activity which comprises administering to amammal an effective amount of a compound having the formula:

or a pharmaceutically-acceptable salt thereof, wherein:

-   R1, R2, and R3 are each independently selected from    -   H, hydroxyl, alkoxy, alkylthio, nitro, amino or amido (each        optionally substituted with alkyl, amino, cycloheteroalkyl,        cycloalkyl fluoro, aryl, heteroaryl, cycloheteroalkyl,        alkylthio, arylthio, cyano, OR′, OC═OR″, C═O—OR′″, or        C═O—NR″″R″″);    -   small alkyl (C1-C10) (optionally C1-C6) (optionally substituted        with alkyl, amino, cycloheteroalkyl, cycloalkyl fluoro, aryl,        heteroaryl, cycloheteroalkyl, alkylthio, P═O(OR″)₂,        CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, arylthio,        cyano, OR″, OC═OR″, C═O—OR′″, or C═O—NR″″R″″);    -   phenyl and mono and disubstituted (at positions 3 and 4) phenyl        (wherein the phenyl ring is independently substituted with        alkyl, trifluoromethyl, mono and di halogen atoms, alkylthio,        alkoxy, nitro, cyano, morphilino, cyclohexyl, phenyl, phenolic,        dioxymethylene, nitro, acetylamino, OR′, P═O(OR″)₂,        CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂);    -   heteroaryl, cycloheteroalkyl and cycloheteroalkyl (each        optionally substituted with alkyl, halogen, alkylthio, alkoxy,        or nitro, OR′, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,        CH(COOR″)_(2,));    -   cycloalkyl (C3-C10) (optionally substituted with alkyl, fluoro,        aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl alkylthio,        arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,        NHCOCOOR″, CH(COOR″)₂, OR′, OC═OR′, C═O—OR″, or C═O—NR′″R″″);    -   alkenyl (C1-C10) (optionally substituted with alkyl, fluoro,        aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio,        arylthio, cyano, P═O(OR′″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,        NHCOCOOR″, CH(COOR″)₂, OR′, OC═OR′, C═O—OR″, or C═O—NR′″R″″);    -   alkadienyl (C1-C10) (optionally substituted with alkyl, fluoro,        aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio,        arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,        NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR5, —C═O—OR″, C═O—NR′″R″″);    -   cycloalkenyl (C4-C10), optionally substituted with alkyl,        fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,        alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,        CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,        C═O—NR′″R″″;    -   bicycloalkyl (C5-C12), optionally substituted with alkyl,        fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,        alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,        CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,        C═O—NR′″R″″;    -   tricycloalkyl (C8-C14), optionally substituted with alkyl,        fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,        alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,        CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,        C—O—NR′″R″″;        where    -   Each R′ is independently:        -   hydrogen;        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, cycloheteroalkyl, cyano, aryloxy,            cycloalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR′)₂,            NHCOCOOR″, CH(COOR″)₂;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, cyano, aryloxy, COOR″, P═O(OR″)₂,            CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   heteroaryl, cycloheteroalkyl, cycloheteroalkyl, optionally            substituted with alkyl, keto, fluoro, alkoxy, alkylthio,            cyano, aryloxy, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl,            cycloheteroalkyl, cyano, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;    -   Each R″ is independently        -   hydrogen,        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, cycloheteroalkyl;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio;        -   heteroaryl, cycloheteroallyl, optionally substituted with            alkyl, keto, fluoro, alkoxy, alkylthio;        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl;    -   Each R′″ is independently        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, COOR″, P═O(OR″)₂, CH₂P—O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio;        -   heteroaryl, cycloheteroalkyl, optionally substituted with            alkyl, keto, fluoro, alkoxy, alkylthio, COOR″, P═O(OR″)₂,            CH₂P═O(OR″)₂, CF₂P═O(OR′″)₂, NHCOCOOR″, CH(COOR″)₂;        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl,            COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,            CH(COOR″)₂; and    -   Each R″″ is independently        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, COOR″, P—O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR′″)₂, NHCOCOOR″, CH(COOR″)₂;        -   heteroaryl, cycloheteroalkyl, optionally substituted with            alkyl, keto, fluoro, alkoxy, alkylthio, COOR″, P═O(OR″)₂,            CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; and        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalky, COOR″,            P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,            CH(COOR″)₂.            And wherein each of R1, R2 and R3 are linked to their            respective core atoms through C, N, O or S of the substiuent            group, provided that if R2 is to be linked through O or S,            then the core atom S is oxidized.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts selected compounds of the invention, together withchemical names.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods and compositions for theinhibition of tyrosine phosphatase activity. Such compositions andmethods will find use in the treatment of diseases caused bydysfunctional signal transduction.

In one aspect the present invention provides a method for inhibitingprotein tyrosine phosphatase activity which comprises administering to amammal an effective amount of a compound having the formula:

wherein R1, R2 and R3 are as further defined below, together with apharmaceutically acceptable salt thereof.

The compounds of the present invention inhibit tyrosine phosphatases,including PTP-1B, and thus improve insulin sensitivity, among otherbenefits. The compounds therefore will find use in preventing ortreating Type 1 and Type 2 diabetes [and associated complications suchas hypertension, ischemic diseases of the large and small blood vessels,blindness, circulatory problems, kidney failure and atherosclerosis],syndrome X, metabolic syndrome, improving glucose tolerance, improvinginsulin sensitivity when there is insulin resistance, improving leptinsensitivity where there is leptin resistance, lowering body weight, andpreventing or treating obesity. In addition, the compounds will beuseful in preventing or treating cancer, neurodegenerative diseases, andthe like.

The compounds of the present invention are generally characterized asnitrogen-containing organosulfur compounds having the formula (I) andtheir pharmaceutically acceptable salts:

wherein:

-   R1, R2, and R3 are each independently selected from    -   H, hydroxyl, alkoxy, alkylthio, nitro, amino or amido (each        optionally substituted with alkyl, amino, cycloheteroalkyl,        cycloalkyl fluoro, aryl, heteroaryl, cycloheteroalkyl,        alkylthio, arylthio, cyano, OR′, OC═OR″, C═O—OR′″, or        C═O—NR″″R″″),    -   small alkyl (C1-C10) (optionally C1-C6) (optionally substituted        with alkyl, amino, cycloheteroalkyl, cycloalkyl fluoro, aryl,        heteroaryl, cycloheteroalkyl, alkylthio, P═O(OR″)₂,        CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, arylthio,        cyano, OR″, OC═OR″, C═O—OR′″, or C═O—NR″″R″″),    -   phenyl and mono and disubstituted (at positions 3 and 4) phenyl        (wherein the phenyl ring is independently substituted with        alkyl, trifluoromethyl, mono and di halogen atoms, alkylthio,        alkoxy, nitro, cyano, rnorphilino, cyclohexyl, phenyl, phenolic,        dioxymethylene, nitro, acetylamino, OR′, P═O(OR″)₂,        CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂), heteroaryl,        cycloheteroalkyl and cycloheteroalkyl (each optionally        substituted with alkyl, halogen, alkylthio, alkoxy, or nitro,        OR′, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,        CH(COOR″)_(2,)),    -   cycloalkyl (C3-C10) (optionally substituted with alkyl, fluoro,        aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl alkylthio,        arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P—O(OR″)₂,        NHCOCOOR″, CH(COOR″)₂, OR′, OC═OR′, C═O—OR″, or C═O—NR′″R″″)    -   alkenyl (C1-C10) (optionally substituted with alkyl, fluoro,        aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio,        arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,        NHCOCOOR″, CH(COOR″)₂, OR′, OC═OR′, C═O—OR″, or C═O—NR′″R″″)    -   alkadienyl (C1-C10) (optionally substituted with alkyl, fluoro,        aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio,        arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P—O(OR″)₂,        NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR5, —C═O—OR″, C═O—NR′″R″″)    -   cycloalkenyl (C4-C10), optionally substituted with alkyl,        fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,        alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,        CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,        C—O—NR′″R″″    -   bicycloalkyl (C5-C12), optionally substituted with alkyl,        fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,        alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,        CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,        C═O—NR′″R″″    -   tricycloalkyl (C8-C14), optionally substituted with alkyl,        fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,        alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,        CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,        C—O—NR′″R″″    -    where    -   Each R′ is independently:        -   hydrogen,        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, cycloheteroalkyl, cyano, aryloxy,            cycloalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,            NHCOCOOR″, CH(COOR″)₂;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, cyano, aryloxy, COOR″, P═O(OR″)₂,            CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   heteroaryl, cycloheteroalkyl, cycloheteroalkyl, optionally            substituted with alkyl, keto, fluoro, alkoxy, alkylthio,            cyano, aryloxy, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl,            cycloheteroalkyl, cyano, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;    -   Each R″ is independently        -   hydrogen,        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, cycloheteroalkyl;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio;        -   heteroaryl, cycloheteroalkyl, optionally substituted with            alkyl, keto, fluoro, alkoxy, alkylthio;        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl;    -   Each R′″ is independently        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio;        -   heteroaryl, cycloheteroalkyl, optionally substituted with            alkyl, keto, fluoro, alkoxy, alkylthio, COOR″, P═O(OR″)₂,            CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl,            COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,            CH(COOR″)₂; and    -   Each R″″ is independently        -   alkyl (C1-C10), optionally substituted with alkyl, keto,            fluoro, alkoxy, alkylthio, aryl, heteroaryl,            cycloheteroalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   aryl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,            CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂;        -   heteroaryl, cycloheteroalkyl, optionally substituted with            alkyl, keto, fluoro, alkoxy, alkylthio, COOR″, P═O(OR″)₂,            CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; and        -   cycloalkyl, optionally substituted with alkyl, keto, fluoro,            alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalky, COOR″,            P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,            CH(COOR″)₂.            And wherein each of R1, R2 and R3 are linked to their            respective core atoms through C, N, O or S of the            substituent group, provided that if R2 is to be linked            through O or S, then the core atom S is oxidized.

In the compounds of formula (I), it is preferred that R1 be an arylgroup optionally substituted with one or more halogen atoms; R2 be aphenylmethyl group optionally substituted at the 3 or 4 position withone or more aryl, perfluoroalkyl (C1-C4), or thiadiazolyl groups; and R3be an benzoyl group optionally substituted with one or moreperfluoroallyl (C1-C4) substituents.

Specific examples of groups that may be represented by R1 include3-bromophenyl and 3,4-dichlorophenyl. Specific examples of groups thatmay be represented by R2 include 4-phenyl phenylmethyl,4-(1,2,3-thiadiazol-4-yl)-phenylmethyl, and3-trifluoromethylphenylmethyl. A specific example of a group representedby R3 includes 3-trifluoromethylbenzoyl.

Alternatively, R1 and R2 can be taken together with the core unit towhich they are attached (formula I) to form a heterocyclic group havingformula (II) as follows:

Where R3 is as defined previously.Of the compounds of formula II, it is preferred that R3 is

-   -   (1) a phenyl group optionally substituted with one to three of        the following and their combinations: halogen, hydroxy, aryloxy,        nitro, carboxylic acid, CF₂P═O(OH)₂, NHCOCOOH, alkyl (C1-C10) or        alkoxy (C1-C10) (optionally substituted with NR1R2, COOH,        cycloheteroalkyl), alkylthio (C1-C4), 2′-hydroxyethoxy,        alkoxycarbonylmethoxy (C1-C4), dialkylamino (C1-C4 where the two        alkyls optionally form a heteroalicyclic ring),        2-(dialkylamino)-2-oxoethoxy (C1-C7 where the two alkyls        optionally form a heteroalicyclic ring), difluoromethoxy,        perfluoroalkyl (C1-C4), perfluoroalkylthio (C1-C4),        perfluoroalkoxy (C1-C4), 2-carboxyvinyl, alkanoyl (C1-C5),        alkoxycarbonyl (C1-C4), alkanoylamino (C1-C8), benzoylamino        (optionally substituted with one or more perfluoroalkyl group        (C1-C4) and/or CF₂P═O(OH)₂, NHCOCOOH,), aryl, aryloxy,        arylcarbonyl, arylmethoxy, arylmethyl in which the methyl group        is substituted with hydroxyl, O(CH₂)_(n)COOH (n=1-5),        S(CH₂)_(n)COOH (n-1-5), (4-carboxy)benzyloxy,        (3-carboxybenzyloxy), or the group ═N—O—CH₂R in which R is        carboxyl, alkoxycarbonyl (C1-C4), hydrogen, or phenyl        (optionally substituted with one or more halogens), or the group        ═N—NHAr in which Ar is a phenyl (optionally substituted with one        or more alkyl groups (C1-C4), and/or a carboxyl group, and/or        CF₂P═O(OH)₂, NHCOCOOH), or the group-Y—(CH₂)_(n)-Z, where Y is O        or S, n is 1, 2, or 3, and Z is hydrogen, methyl, branched alkyl        (C3-C5), cycloalkyl (C3-C6), phenyl (optionally substituted with        one or more of the following: halogen, trifluoroalkyl, carboxy,        alkoxycarbonyl (C1-C4), CF₂P═O(OH)₂, NHCOCOOH, or carboxyl). It        is also preferred that the aryl group in the aryl, aryloxy,        arylcarbonyl, arylmethoxy and arylmethyl substituents within R3        will be phenyl or pyridyl (optionally substituted with one or        more of the following and their combinations: amino,        perfluoroalkyl (C1-C4), CF₂P═O(OH)₂, NHCOCOOH,        CH═CH(CH2)_(n)COOH (n=1-5), 1-tetrazolo, 1-tetrazolo substituted        at the 2 position with carboxyalkyl (n=1-5),        N-(4-carboxyphenylamino)iminomethyl, perfluoroalkoxy (C1-C4),        alkyl (C1-C10) or alkoxy (C1-C10) (optionally substituted with        NR1R2, COOH, cycloheteroalkyl), alkoxycarbonyl (C1-C4), carboxy,        nitro, carboxyalkyl (C1-C7), carboxyalkenyl (C1-C7), formyl,        hydroxyalkyl (C1-C4), halogen, hydroxy, cyano, tetrazole        (optionally substituted with alkyl (C1-C4), carboxyalkyl        (C1-C4), or alkoxycarbonylmethyl (C1-C4)), CONHCH₂(CHOCH₂CH₂O),        or hydroxyalkyl (C1-C4); or    -   (2) a pyridylthio group optionally substituted with one or more        halogen and/or one or more nitro groups, methylenedioxyphenyl,        benzo[3,4-c]1,2,5-oxadiazol-5-yl, 4-oxo-3-hydroquinazolin-2-yl,        or a group having formula (III) as follows:        in which the imidazole ring is optionally substituted with one        or more halogens, and where R5 is as defined for R1, R2 and R3        above.        Of these, it is preferred that R5 is an amino group with two        substituents, where one substituent is arylcarbonyl,        arylmethylcarbonyl, arylsulfonyl, aryldimethyloxycarbonyl, or        aryloxymethylcarbonyl, [where the aryl group is phenyl,        benzox[c]1,2,5-oxadiazol-5-yl, 1-furyl, 2-furyl 1-naphthyl or        2-naphthyl, optionally substituted with one or more of the        following or their combinations: perfluoroalkyl (C1-C4), alkyl        (C1-C4), nitro, alkoxycarbonyl (C1-C4), carboxyl,        carboxyalkyl(C1-C4), CF₂P═O(OH)₂, NHCOCOOH, phenoxy (optionally        substituted with alkoxy (C1-C4), CF₂P═O(OH)₂, NHCOCOOH, COOH,        and/or halogen), or phenylalkoxy (C1-C4)], hydrogen,        CF₂P═O(OH)₂, NHCOCOOH, or a phenyl group [optionally with one or        more of the following substituents or combinations: hydroxy,        halogen, nitro, CF2P═O(OH)₂, NHCOCOOH, carboxy,        carboxyalkyl(C1-C4), carboxyalkylthio (C1-C6), phenyl, alkyl        (C1-C10) or alkoxy (C1-C10) (optionally substituted with NR1R2,        COOH, cycloheteroalkyl), perfluoroalkyl (C1-C4), alkoxycarbonyl        (C1-C4), alkyllhio (C1-C4), phenylalkoxy (C1-C4),        phenylsulfonylamino (each optionally substituted on phenyl with        alkyl (C1-C4)), phenoxy (optionally substituted on phenyl with        nitro, perfluoroalkyl (C1-C4), carboxymethyl, carboxy,        CF₂P═O(OH)₂, NHCOCOOH, alkoxycarbonylmethyl (C1-C4)),        carboxyalkyl(C1-C4), phenylalkylthio (C1-C4, optionally        substituted on phenyl with alkoxy (C1-C4), and/or phenyl),        aminosulfonyl, alkylaminosulfonyl (C1-C4), dialkylaminosulfonyl        (C1-C4 where the two alkyls optionally form a heteroalicyclic        ring).] The second substituent on the amino group forming R5 is        hydrogen, alkyl (C1-C10) or alkoxy (C1-C10) (each optionally        substituted with NR1R2, COOH, CF₂P═O(OH)₂, NHCOCOOH,        cycloheteroalkyl), naphthylalkyl (C1-C4), phenylalkyl (C1-C4,        with the phenyl group optionally substituted with phenyl, alkyl        (C1-C4), halo, amino, amido, keto, CF₂P═O(OH)₂, NHCOCOOH, alkyl        (C1-C10) or alkoxy (C1-C10) (optionally substituted with NR1R2,        COOH, cycloheteroalkyl), nitro, carboxy, perfluoroalkylthio        (C1-C4), halogen, CF₂P═O(OH)₂, NHCOCOOH, 1,2,3-thiadiazolyl,        and/or alkoxy carbonyl (C1-C4)), alkyl (C1-C10), cycloalkyl        (C4-C8, optionally substituted with alkyl (C1-C4)), or indanyl        (optionally substituted with alkyl (C1-C4)). It is also        preferred that R5 is a phenyhmethylthio group, optionally        substituted with one or more halogens on the phenyl ring, or        2-oxo-2-(2-naphthylethylthio) optionally substituted with one or        more alkyl groups (C1-C4).

Specific examples of groups that may be represented by R3 include:3-nitrophenyl, 3,5-dinitrophenyl, 3,4-dihydroxyphenyl, 2-chlorophenyl,2-trifluoromethylphenyl, 3-carboxyphenyl, 3-methylphenyl,3-methoxyphenyl, 3-ethoxyphenyl, 3-trifiuoromethoxyphenyl,4-carboxyphenylmethyl,3-(3-(N-(4-carboxyphenylamino)iminomethyl)phenoxy)phenyl,3-(3-(6-carboxy-hex-1-enyl)phenoxy)phenyl,3-(3-carboxyphenylmethoxy)-5-(phenylmethoxy)phenyl,3-(3-carboxyphenoxy)phenyl, 3,5-bis(phenylmethoxy)phenyl,3,5-bis(3-methoxyphenylmethoxy)phenyl,3,5-bis(3-trriluoromethylphenylmethoxy)phenyl,3-(3-((2-carboxybutyl)-1-tetrazolo))phenoxy)phenyl,3-((4-carboxyphenylamino)imino)(3-trifluoromethylphenyl)methyl)phenyl,-3-((carboxymethylthio)(3-trifluoromethylphenyl)methyl)phenyl,3-(3-(1-hydroxy, 2,2 difluoro,2-(dihydroxyphosphono)ethyl)phenoxy)phenyl, 3-trifluoromethylthiophenyl,3-(4-methylpentanoylamino)phenyl), 4-dimethylaminophenyl,4-ethoxyphenyl, 4-methylthiophenyl, 4-difluoromethoxyphenyl,4-(2-carboxyvinyl)phenyl, 3,4-dinethoxyphenyl, 3-chloro-4-bromophenyl,3-bromo-4-chlorophenyl, 3-nitro-4-morpholinophenyl,3-phenylmethoxyphenyl, 3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenoxy,3-(1-naphthylsulfonylamino)phenyl, 4-phenylphenyl, 3,5-dimethoxyphenyl,3,4-methylenedioxyphenyl, 3-phenylmethoxy-4-methoxyphenyl,benzo[3,4-c]1,2,5-oxadiazol-5-yl, 4-oxo-3-hydroquinazolin-2-yl,3-(2′-hydroxyethoxy)phenyl, 3-(ethoxycarbonylmethoxy)phenyl,3-n-butoxyphenyl, 4-ethylaminophenyl, 4-phenoxyphenyl,3-(3′-trifluoromethylphenoxy)phenyl, 3-(3′aminophenoxy)phenyl,3,5-bis(3′trifluoromethylphenoxy)phenyl,6-(3′trifluoromethylphenoxy)-2-pyridyl,3-(3′methoxycarbonylphenoxy)phenyl,3-(3′trifluoromethylphenoxy)-5-hydroxyphenyl,3-(3′-hydroxyphenoxy)phenyl,3-(3′-(1-ethoxycarbonylmethyl-1,2,3,4-tetrazol-5-yl)phenoxy)phenyl,3-(4′-t-butylphenoxy)phenyl, 3-(3′carboxyphenoxy)phenyl,3-(3′nitrophenoxy)phenyl, -(3′carboxymethylphenoxy)phenyl,3-(4′methoxyphenoxy)phenyl, 3-(4′methylphenoxy)phenyl,3-(3′,5′-dichlorophenoxy)phenyl, 3-(3′,4′-dichlorophenoxy)phenyl,3-(4′hydroxyphenoxy)phenyl, 3-(3′cyanophenoxy)phenyl,-3-(3′-(tetrazole-1-yl)phenoxy)phenyl,3-(3′-(N-(1,3-dioxolan-2-ylmethyl)carbamoyl)phenoxy)phenyl,3-(3′-hydroxymethylphenoxy)phenyl, 3-(3′(2″-carboxyethyl)phenoxy)phenyl,3-(4′-t-butylphenylmethoxy)phenyl,4-(3′,5′-bis(trifluoromethyl)benzoylamino)phenyl,3-(3′-trifluoromethoxyphenylmethoxy)phenyl,3-(3′-trifluorophenylmethoxy)phenyl,3-(3′-trifluoromethylbenzoyl)phenyl,3-((3′-trifluoromethylphenyl)hydroxymethyl)phenyl,3-[3′-[2-aza-2-(ethoxycarbonylmethoxy)vinyl]phenoxy]phenyl,3-[3′-[2-aza-2-(carboxymethoxy)vinyl]phenoxy]phenyl,3-[3′-[2-aza-2-(4″-carboxyphenylamino)vinyl]phenoxy]phenyl, 3-{ethoxy[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(carboxymethoxy)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(ethoxylcarbonylmethoxy)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(ethoxylcarbonylmethyl)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(carboxymethyl)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(2′,4′-dichlorophenylmethylthio)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-(1-(3′-trifluoromethylphenyl)-2-aza-2-(4″-carboxyphenylamino)vinyl)phenoxy,3-(3′-(6-carboxyhex-1-enyl)phenoxy)phenyl,3-{(3-methyl-1-butylthio)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(2-carboxyethylthio)[3-(trifluoromethyl)phenyl]methyl}phenyl,3-{(ethoxycarbonylmethoxy)[3-(trifluoromethyl)phenyl]methyl}phenyl,3,5-bis(phenylmethoxy)phenyl,(4,5-dichloroimidazolyl)methyl]phenoxy}methyl),2-nitro-4-bromo-(2-pyridylthio).

Specific examples of groups that may be represented by R5 include3-bromophenylamino, 4-bromophenylamino, 4-fluorophenylamino,3-nitrophenylamino, 4-nitrophenylamino, 3-fluorophenylamino,4-aminosulfonylphenylamino, 3-methylphenylamino, 3-hydroxyphenylamino,3-carboxyphenylamino, 4-ethoxycarbonylphenylamino, 3-methoxyphenylamino,3-methoxycarbonylphenylamino, 4-carboxyphenylamino,3-trifluoromethylphenylamino, 4-acetylphenylamino, 4-ethylphenylamino,4-isopropylphenylamino, 3,5-dinitrophenylamino, 4-(n-butyl)-phenylamino,4-(n-decyl)amino, 4-ethoxycarbonylphenylamino,4-methoxycarbonylphenylamino, 3,(4-carboxymethylphenoxy)phenylamino,4-piperidinosulfonylphenylamino, 4-(4-nitrophenoxy)phenylamino,3-(4-phenylphenylmethylthio)phenylamino,3-(2-phenylphenylmethylthio)phenylamino, 3-carboxymethylphenylamino,3-(2-carboxyethyl)phenylamino, 3-(3-trifluoromethylphenoxy)phenylamino,naphthalene-1-sulfonylamino, naphthalene-2-sulfonylamino,3-(4-methoxylphenylmethylthio)phenylamino,3-(3-phenylpropylthio)phenylamino, 2,5-dibromophenylamino,3-chloro-4-fluorophenylamino, 2,3-dichlorophenylamino,3,4-dichlorophenylamino, 3,4-dibromophenylamino,2-chloro-5-nitrophenylamino, 2,4-dimethoxy-5-chlorophenylamino,3-chloro-4-methylphenylamino, 3-chloro-4-bromophenylamino,3-methyl-4-bromophenylamino, 4-(phenylsulfonylamino)phenylamino,4-(4′-methylphenylsulfonylamino)-phenylamino,(3-chloro-4-bromophenyl)(2-phenylmethyl)amino,(3-chloro-4-bromophenyl)(2-trifluoromethylthiophenylmethyl)amino,(3-chloro-4-bromophenyl)(4-t-butylphenylmethyl)amino,(2,3,4,5-tetrachlorophenyl)(4-t-butylphenylmethyl)amino,(3,4-dichlorophenyl)(3-methoxycarbonylphenyl)methyl)amino,(3,4-dichlorophenyl)(4-methoxycarbonylphenyl)methyl)amino,(3,4-dichlorophenyl)(3-carboxyphenyl)methyl)amino,3-phenylmethoxyphenylamino, 3-chloro-4-methylphenylamino,2,3,4,5-tetrachlorophenylamino,(3,4-dichlorophenyl)[(4-carboxyphenyl)methyl]amino,(3,4-dichlorophenyl)[(4-methoxycarbonylphenyl)methyl]amino,(phenylmethyl)(3-chloro-4-bromophenyl)amino,(phenylmethyl)(3-bromophenyl)amino,(3,4-dichlorophenyl)[(4-phenylphenyl)methyl]amino,(3,4-dichlorophenyl)[4-(t-butylphenyl)methyl]amino,(3,4-dichlorophenyl)[(3-nitrophenyl)methyl]amino,(3,4-dichlorophenyl)[2-naphthylmethyl]amino,(methyl)(3,4-dichlorophenyl)amino, 3-trifluoromethylbenzoylamino,3,5-bistrifluoromethylbenzoylamino, 3-methoxycarbonylbenzoylamino,3-nitrobenzoylamino, 4-t-butylphenoxyacetylamino,2-(4-chlorophenoxy)-2-methylpropanoylamino,benzo[c]1,2,5-oxadiazol-5-yl-amino,2-(4-methoxyphenoxy)-5-nitrobenzoylamino,5-(3,5-dichlorophenoxy)-2-furoylamino, 2-methyl-3-chlorobenzoyl,4-(phenylmethoxy)phenylacetylarmino, 1-naphthoylamino,2-(4-methylphenyl)ethylamino, 1-napthylmethylamino, 2-indanylamino,3,3,5-trimethylcyclohexylamino, 2-heptylamino,3,4-dichlorophenylmethylthio, 2,6-dichlorophenylmethylthio, and2-oxo-2-(2-naphthyl)ethylthio.

Alternatively, R1 and R2 can be taken together with the core unit towhich they are attached (formula I) to form a heterocyclic group havingformula (IV) as follows:

Wherein R3 is as defined previously.

Of these, it is preferred that that R3 be an arylamino group in whichthe aryl group is phenyl or pyridyl (optionally substituted with one ormore of the following groups: phenyl, halogen, or hydroxy), or aphenylamino group (optionally substituted on the phenyl with one or moreof the following: halogen, phenoxy, perfluoroalkyl (C1-C4), alkyl(C1-C4), or nitro), or a phenyl group optionally substituted with one ormore nitro groups.

Specific examples of groups that may be represented by R3 include2-hydroxy-5-chlorobenzoylamino, 2-hydroxy-5-bromobenzoylamino,3-pyridinecarboxylamino, 4-bromobenzoylamino,2-nitro-5-chlorobenzoylamino, 2,6-dimethoxy-3,5-dichlorobenzoylamino,3-bromophenylamino, 4-phenoxyphenylamino, 3,4-dichlorophenylamino,2,4,5-trichlorophenylamino, 3,5-dichlorophenylamino,bis(trifluoromethyl)phenylamino, and 3-nitrophenyl.

Wherein R6 is as defined above for R1, R2 and R3.

Of these, it is preferred that that R6 be hydrogen, naphthyl, or phenyl[optionally substituted with one or more of the following: phenyl,alkoxy (C1-C4), alkyl (C1-C4), nitro, cyano, halogen, dialkylamino(C1-C4, with the two alkyl groups optionally joined to form aheterocycle), alkoxycarbonyl (C1-C4), benzoyloxy].

Specific examples of groups that may be represented by R6 includehydrogen, 4-phenylphenyl, 3-methoxyphenyl, 4-methylphenyl,4-nitrophenyl, 4-cyanophenyl, 3-chloro-4-methylphenyl,3,4-dichlorophenyl, 3-methyl-4-chlorophenyl, 4-diethylaminophenyl,4-N-pyrrolidinophenyl, 2-(ethoxycarbonyl)phenyl, 3-benzoyloxyphenyl,4-benzoyloxyphenyl, 2-naphthyl.

Wherein R7 is as defined above for R1, R2 and R3.

Of these, it is preferred that that R7 be hydrogen, alkyl (C1-C4),benzoyl (optionally substituted with one or more of the following ortheir combinations: halogen, nitro, alkoxy (C1-C4)), phenyl (optionallysubstituted with one or more halogen or nitro group), phenylamino(optionally substituted with one or more halogens), or2H,3H,4H-benzo[3,4-b]1,4-dioxepan-7-yl (optionally substituted with oneor more alkyl(C1-C4)).

Specific examples of groups that may be represented by R7 includehydrogen, methyl, benzoyl, 4-bromobenzoyl, 3,4-dichlorobenzoyl,2-nitrophenyl, 3-nitrophenyl, 4-chlorophenyl,2H,3H,4H-benzo[3,4-b]1,4-dioxepan-7-yl, and 3-bromophenylamino.

Alternatively, R1 and R2 are linked through an aromatic ring, and takentogether with the N═CR3—S unit to which they are attached, form atricyclic heterocyclic group having formula (V) as follows:

Where R3 is as defined above for R1, R2 and R3.Where R9 is as defined above for R1, R2 and R3.Where R10 is as defined above for R1, R2 and R3.Where R11 is as defined above for R1, R2 and R3.

Of these, it is preferred that that R3 be phenylamino (optionallysubstituted on phenyl with one or more of the following: halogen,alkyl(C1-C4), perfluoroalkyl(C1-C4)). It is preferred that that R9 behydrogen or alkyl(C1-C4). It is preferred that that R10 and R11,independently, be H, alkyl (C1-C4), or halogen. In a specific example,R3 is 2,4,5-trichlorophenylamino, and R9, R10, and R11 are hydrogen.

Alternatively, R1 and R2, taken together with the N═CR3—S unit to whichthey are attached, form a heterocyclic group having formula (VI) asfollows:

Where R1 is as defined above for R1, R2 and R3.Where R12 is as defined above for R1, R2 and R3.Where R13 is as defined above for R1, R2 and R3.Of these, it is preferred that that R3 be phenyl, optionally substitutedwith one or more of the following: Halogen, nitro, alkyl (C1-C10),CF₂P═O(OH)₂, or alkoxy (C1-C10) (optionally substituted with NR1R2,COOH, cycloheteroalkyl), phenoxy (optionally substituted withperfluoroalkyl(C1-C4), carboxy, carboxymethyl,N-(4-carboxyphenylamino)iminomethylene, CF₂P═O(OH)₂, alkyl (C1-C10) oralkoxy (C1-C10) (optionally substituted with NR1R2, COOH,cycloheteroalkyl), and/or halogen). It is preferred that that R12 bealkyl (C1-C10, optionally substituted with carboxyl or CF₂P═O(OH)₂,) oralkoxy (C1-C10) (optionally substituted with NK1R2, COOH,cycloheteroalkyl), naphthylalkyl(C1-C4), or phenylalkyl(C1-C4,optionally substituted on phenyl with carboxyalkyl, carboxy,CF₂P═O(OH)₂, phenyl, alkyl (C1-C10) or alkoxy (C1-C10) (optionallysubstituted with NR1R2, COOH, cycloheteroalkyl), oralkoxycarbonylalkyl(C1-C4)). It is preferred that that R13 be branchedalkyl (C1-C5), alkyl (C1-C5), cycloalkyl (C3-C7), phenyl (optionallysubstituted with one or more of the following or their combinations:halogen, alkoxycarbonyl(C1-C4), alkyl (C1-C10), piperidinosulfonyl, oralkoxy (C1-C10) (optionally substituted with NR1R2, COOH,cycloheteroalkyl)), cycloalkyl, alkyl (C1-C10) or alkoxy (C1-C10)(optionally substituted with NR1R2, COOH, cycloheteroalkyl), heteroaryl,and cycloheteroaryl. Specific examples of R3 are 3-nitrophenyl,3-ethoxyphenyl, 3-phenoxyphenyl, 3-(3-carboxyphenoxy)phenyl,4-carboxyphenyl,3-(3-(N-(4-carboxyphenylamino)iminomethyl)phenoxy)phenyl,3-(4-(dihydroxyphosphonodifluoromethyl)phenoxy)phenyl, and3-(3-trifluoromethylphenoxy)phenyl. Specific examples of R12 includemethyl, phenylmethyl, 3-methoxyphenylmethyl,3-(methoxycarbonyl)phenylmethyl, 2-trifluoromethylphenylmethyl,4-carboxyphenylmethyl, 4-(carboxymethyl)phenylmethyl, carboxylmethyl,4-(dihydroxyphosphonodifluoromethyl)-butyl,4-(dihydroxyphosphonodifluoromethyl)phenylmethyl,4-(1,2,3-thiadiazole-4-yl)phenylmethyl, 4-t-butylphenylmethyl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-naphthylmethyl, and4-phenylphenylmethyl. Specific examples of R13 include 3-bromophenyl,3,4-dichlorophenyl, 3-chloro-4-bromophenyl, isopropyl,4-(piperidinosulfonyl)phenyl, 3-(3-trifluoromethylphenoxy)phenyl, and3-methoxycarbonylphenyl.

Alternatively, R1 and R3, taken together with the N═C—SR2 unit to whichthey are attached, form a heterocyclic group having formula (VII) asfollows:

Where R2 is as defined above for R1, R2 and R3.Where R14 is as defined above for R1, R2 and R3.Where R15 is as defined above for R1, R2 and R3.Of these, it is preferred that that R2 be 2-phenyl-2-oxoethylthio,optionally substituted on phenyl with one or more of the following ortheir combinations: nitro, halogen, alkyl (C1-C4). It is preferred thatthat R14 be phenyl, optionally substituted with one or more alkyl groups(C1-C6). It is preferred that that R15 be hydrogen or alkyl(C1-C4). Aspecific example of R2 is 2-(4-nitrophenyl)-2-oxoethylthio. A specificexample of R14 is 4-n-pentylphenyl. A specific example of R15 ishydrogen.

Alternatively, R1 and R3, taken together with the N═C—SR2 unit to whichthey are attached, form a bicylic heterocyclic group having formula(VIII) as follows:

Where R2 is as defined above for R1, R2 and R3.Where R18 is as defined above for. R1, R2 and R3.Where R19 is as defined above for R1, R2 and R3.Of these, it is preferred that that R2 be 2-phenyl-2-oxyethyl,optionally substituted on phenyl with one or more of the following ortheir combinations: halogen, alkyl (C1-C4). It is preferred that thatR18 be amino, optionally substituted with one or two alkyl groups(C1-C4). It is preferred that that R19 be benzoyl, optionallysubstituted with one or more of the following or their combinations:halogen, alkyl (C1-C4).

Alternatively, R1, R2 and R3, taken together with the N═C—S unit towhich they are attached, form a bicyclic heterocyclic group havingformula (IX) as follows:

Where R20 is as defined above for R1, R2 and R3.Where R21 is as defined above for R1, R2 and R3.Where R22 is as defined above for R1, R2 and R3.Of these, it is preferred that that R20 be phenyl, optionallysubstituted with one or more of the following or their combinations:halogen, alkyl (C1-C4). It is preferred that that R21 be hydrogen, alkyl(C1-C4), or phenyl, optionally substituted with one or more of thefollowing or their combinations: hydroxy, alkyl (C1-C4). It is preferredthat that R2 be hydrogen, phenylthioacyl (optionally substituted withone or more halogens), phenylaminoacylamino (optionally substituted onphenyl with one or more halogens), phenylhydrazinoacylamino (optionallysubstituted on phenyl with one or more halogens).A specific examples of R20 is 4-chlorophenyl. Specific examples of R21are methyl or 2,4-dihydroxyphenyl. Specific examples of R22 arehydrogen, 2,4-difluorophenylthioacyl, phenylaminocarbonylamino,2,4-dichlorophenylaminocarbonylamino, and2,4-dichlorophenylhydrozinocarbonylamino.

Alternatively, R1, R2 and R3, taken together with the N═C—S unit towhich they are attached, form a bicyclic heterocyclic group havingformula (X) as follows:

Where R23 is as defined above for R1, R2 and R3.Where R24 is as defined above for R1, R2 and R3.Of these, it is preferred that that Y be nitrogen or carbon substitutedwith an aromatic group which consists of phenyl (optionally substitutedwith one or more of the following or their combinations: halogen,phenyl, alkoxy (C1-C4)), phenylisoxazolyl, optionally substituted withone or more halogens, or 2H,3H,4H-benzo[3,4-b]1,4-dioxepan-7-yl,optionally substituted with one or more alkyl groups (C1-C4). It ispreferred that that R23 be hydrogen, alkyl (C1-C4), or phenyl,optionally substituted with one or more halogens. It is preferred thatthat R24 be phenyl, optionally substituted with one or more of thefollowing: halogen, nitro, alkoxy (C1-C4), or alkyl (C1-C4).Specific examples of Y include nitrogen and carbon substituted with4-bromophenyl, 4-chlorophenyl, 4-phenylphenyl,3-(2,4-dichlorophenyl)isoxazol-5-yl], and2H,3H,4H-benzo[3,4-b]1,4-dioxepan-7-yl. Specific examples of R23 includehydrogen, 4-chlorophenyl, or in which R1 and R2, together with theN═CR3—S unit to which they are attached, form a bicyclic heterocyclicgroup as follows:

Where R25 is as defined above for R1, R2 and R3.Where R26 is as defined above for R1, R2 and R3.Of these, it is preferred that that R3 be benzoylamino, optionallysubstituted on the phenyl ring with one or more of the following ortheir combinations: halogen, alkyl (C1-C4), and optionally substitutedon nitrogen with alkyl (C1-C4). It is preferred that that R25 be phenyl,optionally substituted with one or more of the following or theircombinations: halogen, alkyl (C1-C4). It is preferred that that R26 beperfluoroalkyl (C1-C4).A specific example of R3 is 4-chlorobenzoylamino. A specific example ofR25 is phenyl. A specific example of R26 is trifluoromethyl.

The compounds of the present invention generally contain one or moreasymmetric centers and thus give rise to optical isomers anddiastereomers. The scope of the present invention includes all possibleisomers and diastereomers, as well as their racemic and resolved,enantiomerically pure forms.

Certain of the present compounds contain olefinic double bonds and,unless specified to the contrary, the compounds of the present inventioninclude both the E and Z geometric isomeric forms.

Pro-Drug Compounds of the Invention

Alternatively, the compounds of the present invention can be furthermodified to act as prodrugs. It is a well-known phenomenon in drugdiscovery that compounds such as enzyme inhibitors can display potencyand selectivity in in vitro assays, yet not readily manifest the sameactivity in vivo. This lack of “bioavailability” may be due to a numberof factors, such as poor absorption in the gut, first-pass metabolism inthe liver, and poor uptake in the cells. Although the factorsdetermining bioavailability are not completely understood, there aremany techniques known by those skilled in the art to modify compounds,which are potent and selective in biochemical assays but show low or noactivity in vivo, into drugs that are biologically and therapeuticallyactive.

It is considered to be within the scope of the invention to modify anyof the compounds of the invention (termed the ‘original compound’) byattaching chemical groups that will improve the bioavailability of theoriginal compound. Examples of said modifications include changing ofone or more carboxy groups to esters (for instance methyl esters, ethylesters, acetoxymethyl esters or other acyloxy-methyl esters). Compoundsof the invention so modified by attaching chemical groups are termed‘modified compounds.’

Other examples of modified compounds are compounds that have beencyclized at specific positions (‘cyclic compounds’) which upon uptake incells or mammals become hydrolyzed at the same specific position(s) inthe molecule to yield the compounds of the invention, the originalcompounds, which are then said to be ‘non-cyclic’. For the avoidance ofdoubt, it is understood that the latter original compounds in most caseswill contain other cyclic or heterocyclic structures that will not behydrolyzed after uptake in cells or mammals.

Generally, said modified compounds will not show a behavior inbiochemical assays similar to that of the original compound, i.e., thecorresponding compounds of the invention without the attached chemicalgroups or said modifications. Said modified compounds may even beinactive in biochemical assays. However, after uptake in cells ormammals these attached chemical groups of the modified compounds may inturn be removed spontaneously or by endogenous enzymes or enzyme systemsto yield compounds of the invention, original compounds. ‘Uptake’ isdefined as any process that will lead to a substantial concentration ofthe compound inside cells or in mammals. After uptake in cells ormammals and after removal of said attached chemical group or hydrolysisof said cyclic compound, the compounds may have the same structure asthe original compounds and thereby regain their activity and hencebecome active in cells and/or in vivo after uptake.

A number of techniques well known to those skilled in the art may beused to verify that the attached chemical groups have been removed orthat the cyclic compound has been hydrolyzed after uptake in cells ormammals. One example of such techniques is as follows: A mammalian cellline, which can be obtained from the American Type Culture Collection(ATCC) or other similar governmental or commercial sources, is incubatedwith a modified compound. After incubation under appropriate conditions,the cells are washed, lysed and the lysate is isolated. A number ofdifferent procedures, well known to those skilled in the art, may inturn be used to extract and purify the modified compound (or ametabolite thereof) (the ‘purified compound’) from the lysate. Themodified compound may or may not retain the attached chemical group orthe cyclic compound may or may not have been hydrolyzed. Similarly, anumber of different procedures may be used to structurally andchemically characterize the purified compound. Since the purifiedcompound has been isolated from said cell lysate and hence has beentaken up by said cell line, a comparison of the structurally andchemically characterized compound with that of the original compound(i.e. without the attached chemical group or other modification) willprovide information on whether the attached chemical group as beenremoved in the cell or if the cyclic compound has been hydrolyzed.

As a further analysis, the purified compound may be subjected to enzymekinetic analysis as described in detail in the present description. Ifthe kinetic profile is similar to that of the original compound withoutthe attached chemical group, but different from the modified compound,this result confirms that the chemical group has been removed or thecyclic compounds has been hydrolyzed. Similar techniques may be used toanalyze compounds of the invention in whole animals and mammals.

A preferred form of prodrug is acetoxymethyl esters of the compounds ofthe present invention, which may be prepared by the following generalprocedure (C. Schultz et al., J. Biol. Chem. 1993, 268:6316-6322):

A carboxylic acid (1 eq) is suspended in dry acetonitrile (2 mL/0.1mmol). Diisopropyl amine (3.0 eq) is added followed by bromomethylacetate (1.5 eq). The mixture is stirred under nitrogen overnight atroom temperature. Acetonitrile is removed under reduced pressure toyield an oil, which is diluted in ethylacetate and washed with water(3×). The organic layer is dried over anhydrous magnesium sulfate.Filtration, followed by solvent removal under reduced pressure, affordsa crude oil. The product is purified by column chromatography on silicagel, using an appropriate solvent system.

As used herein, the term “attached” (or “−” or “bound”) signifies astable covalent bond.

As used herein, the term “alkyl” includes a straight or branched chainsaturated hydrocarbon group having from 1 to 20 carbons such as methyl,ethyl, isopropyl, n-butyl, s-butyl, t-butyl, n-amyl, isoamyl, n-hexyl,n-octyl and n-decyl, and includes such cyclic and alkyl-substitutedcyclic alkyls that are possible within the given carbon numberlimitations.

As used herein, the terms “alkenyl” and “alkynyl” include straight orbranched chain hydrocarbon groups having from 2 to 10 carbons andunsaturated by a double or triple bond respectively, such as vinyl,allyl, propargyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-2-ynyl,1-methylbut-2-enyl, pent-1-enyl, pent-3-enyl, 3-methylbut-1-ynyl,1,1-dimethylallyl, hex-2-enyl and 1-methyl-1-ethylallyl.

As used herein, the term “phenylalkyl” includes the aforementioned alkylgroups substituted by a phenyl group such as benzyl, phenethyl,phenopropyl, 1-benzylethyl, phenobutyl and 2-benzylpropyl.

As used herein, the term “aryl” includes a monocyclic or bicyclic rings,wherein at least one ring is aromatic including aromatic hydrocarbons orhetero-aromatic hydrocarbons.

As used herein, the term “hydroxy-alkyl” includes the aforementionedalkyl groups substituted by a single hydroxyl group such as2-hydroxybutyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl,1-hydroxybutyl and 6-hydroxyhexyl.

As used herein, the terms “alkylthio, alkenylthio, alkynylthio,alkylthio, hydroxy-alkylthio and phenyl-alkylthio” mean theaforementioned alkyl, alkenyl, alkynyl, hydroxy-alkyl and phenyl-alkylgroups linked through a sulfur atom to group R.

As used herein, the term “substituted” means that the group in question,e.g., alkyl group, aryl group, etc., may bear one or more substituentsincluding but not limited to halogen, hydroxy, cyano, amino, nitro,mercapto, carboxy and other substituents known to those skilled in theart.

As used herein, the term “saturated” means an organic compound withneither double nor triple bonds, and the term “unsaturated” means anorganic compound containing either double or triple bonds.

Procedures for the Synthesis of Compounds and Intermediates

Procedure A

(3-[(2-Phenylphenyl) methylthio] phenylamine): 2-phenyl benzylbromide(2.47 g; 10 mmol) is added slowly to a stirred solution of3-aminotiophenol (1.25 g; 10 mmol) in the mixture of ethanol (20 mL) and1M NaOH (10 mL). The mixture is stirred for 30 minutes, the solventevaporated and the residue is purified using a Biotage column. Theproduct is eluted with EtoAc/Hexanes (4/1). Yield: 1.8 g (62%).

¹H NMR: (300 MHz, CDCl₃) 7.39δ (7H, m); 7.31δ (3H, m); 7.00δ (1H, t);6.49δ (1H, s); 6.48δ (1H, d); 4.07δ (2H, s).

Procedure B

A mixture of 3-bromobenzaldehyde (1.000 g; 5.4 mmol), methyl3-hydroxybenzoate (987 mg; 6.5 mmol) and potassium carbonate (1.494 g;10.8 mmol) in dry pyridine (8 mL) is stirred under argon at RT. Copper(II) oxide (860 mg; 10.8 mmol) is added and the reaction mixture isrefluxed for 12 hours. After cooling to RT, CH₂Cl₂ (SOmL) is added andthe mixture is filtered through celite. The filter cake is washed withfresh CH₂Cl₂ (50 mL). The combined organics are concentrated in vacuo.The residue is purified by flash chromatography (ethyl acetate/hexanes,1:10 to 1:4) to yield methyl 3-(3-carbonylphenoxy)benzoate (776 mg; 56%)as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.97 (1H, s), 7.85 (1H, d, J=6.9 Hz),7.69-7.24 (7H, m), 3.91 (3H, s).

Procedure C

3-[(2-phenylphenyl) methylthio]benzeneisothiocyanate: Thiophosgene (1.37g; 12 mmol) is slowly added to a solution of 3-[(2-Phenylphenyl)methylthio]phenyl amine in a mixture of water (60 mL) andMethylenechloride (45 mL). The mixture is stirred under nitrogen at RTfor two hours. The aqueous layer is separated, and the methylenechlorideis washed with water. The organic layers are dried over anhydrous sodiumsulfate and rotovaped to provide a brown oil. Yield: 2.2 g (70%).

Procedure D

The hydrazine hydrate (7.12 mL; 147 mmol) is dissolved in 220 mL ofethanol. This solution is stirred at 0° C. and3,4-dichlorobenzenisothiocyanate (20.00 g; 98 mmol) is added dropwise,and the reaction mixture is warmed to RT and stirred for two hours.After being cooled to 0° C., the mixture is filtered and the solidwashed by cold ethanol (40 mL). The solid is crystallized from ethanolto yield ([(3,4-dichlorophenyl)amino]hydrazinomethane-1-thione) (12.702g; 55%) as a white solid.

¹H NMR (300 MHz, d₆-DMSO): δ 9.40 (1H, s), 8.19 (1H, s), 7.69 (1H, d),7.53 (1H, d), 5.30 (3H, br s).

Procedure E

(3-(1,3-Dioxolan-2-yl)phenyl)[3-(trirluoromethyl)phenyl]methan-1-ol) A1.0 mL aliquot of 2-(3-bromophenyl)-1,3-dioxolane is added intomagnesium (610 mg; 25 mmol) and THF (5 mL) under Argon. After thereaction is started, the residue of 2-3-bromophenyl)-1,3-dioxolane(total: 5.73 g; 25 mmol) in TBP (20 mL) is added dropwise into thereaction mixture. The resulting solution is stirred at room temp for sixhours, and then at 50-60° C. for 20 hours. After the mixture is cooled,a solution of 3-(trifluoromethyl)-benzaldehyde (4.35 g; 25 mmol) in TBF(20 mL) is added dropwise and the reaction is stirred at room temnp for24 hours. The NH₄Cl saturated solution (50 mL) is added and stirred for30 minutes. The organic layer is separated and the aqueous layer isextracted with ethyl acetate (2×100 mL). The organic layers are combinedand dried over anhydrous Na₂SO₄. The solvent is removed and the residueis purified by column chromatography on silica gel. Eluting with ethylacetate/hexanes (20:80) provide a colorless oil (3.23 g; 40%) as(3-(1,3-dioxolan-2-yl)phenyl)[3-(trifluoromethyl)phenyl]-methan-1-ol: MS307.0 (M−17).

Procedure F

(Methyl-4-[(hydrazinylthioxomethyl) amino]benzoate: A mixture of methyl4-isothiocyanato benzoate (193 mg; 1 mmol) and hydrazine (10 mg; 2 mmol)are stirred in toluene (7.5 mL) at RT for two hours. The solid isfiltered, washed with a small volume of ethanol and hexanes and dried invacuum. Yield: 192 mg (85%).

¹H NMR: (300 MHz, DMSO-d₆) 9.66δ (1H, s); 7.86δ (5H, m); 3.83δ (3H, s).

Procedure G

N-(3-bromophenyl)-2-[(3-nitrophenyl)carbonylamino]acetamide3-nitrohippuric acid (250 mg; 1.116 mmol) is dissolved in methylenechloride (5 mL) containing a catalytic amount of DMAP,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (640 mg;3.34 mmol) and 3-bromoaniline (290 mg; 1.685 mmol). The solution isstirred for 18 hours at 25° C., diluted with enough methylene chlorideto dissolve the resulting precipitate, and washed three times with 2Nhydrochloric acid (aqueous) and saturated aqueous sodium chloride. Theorganic layer is dried with sodium sulfate, filtered, and stripped ofsolvent in vacuo. The resulting yellow solid is washed with 1:1acetone/methylene chloride, then with 1:1 acetone/methanol to yield thetitle compound as a gray solid.

Procedure H

Iron powder (5.03 g; 56 mmol), water (5 mL) and hydrochloric acid (0.1mL; 36 mmol) are added consecutively to a solution of methyl2-[4-(3-nitrophenoxy)phenyl]acetate (1.3 g; 4.5 mmol) in ethanol (20mL). After stirring at 95° C. for four hours, the solid is filteredwhile still hot and the filtrate is stripped of solvent in vacuo toyield methyl 2-[4-(3-aminophenoxy)phenyl]acetate as an oil. Yield: 1.1 g(95%).

¹H NMR: (300 MHz, DMSO-d₆) 7.24δ (2H, d); 6.96δ (3H, m); 6.31δ (1H, d);6.13δ (1H, s); 6.10δ (1H, d); 5.23δ (2H, d); 3.65δ (2H, s); 3.62δ (3H,s).

Prophylaxis and Treatment of Disease

The compounds of the present invention inhibit tyrosine phosphatases,including PTP-1B, and thus improve insulin sensitivity, among otherbenefits. The compounds therefore will find use in preventing ortreating Type 1 and Type 2 diabetes, improving glucose tolerance,improving insulin sensitivity when there is insulin resistance, loweringbody weight, and preventing or treating obesity. In addition, thecompounds will be useful in preventing or treating cancer,neurodegenerative diseases, and the like.

The present compounds may also be administered in combination with oneor more further pharmacologically active substances e.g., selected fromantiobesity agents, antidiabetics, antihypertensive agents, agents forthe treatment and/or prevention of complications resulting from orassociated with diabetes and agents for the treatment and/or preventionof complications and disorders resulting from or associated withobesity.

In a further aspect of the invention the present compounds may beadministered in combination with one or more antiobesity agents orappetite regulating agents. Such agents may be selected from the groupconsisting of CART (cocaine amphetamine regulated transcript) agonists,NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexinantagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropinreleasing factor) agonists, CRF BP (corticotropin releasing factorbinding protein) antagonists, urocortin agonists, B3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR(peroxisome proliferator activated receptor) modulators, RXR (retinoid Xreceptor) modulators or TR B agonists.

In one embodiment of the invention the antiobesity agent is leptin. Inother embodiments, the antiobesity agent is dexamphetamine oramphetamine, fenfluramine or dexfenfluramine, sibutramine, orlistat,mazindol or phentermine.

Suitable antidiabetics comprise insulin, GLP-1 (glucagons likepeptide-1) derivatives such as those disclosed in WO 98/08871, which isincorporated herein by reference, as well as orally active hypoglycemicagents. The orally active hypoglycemic agents preferably comprisesulphonylureas, biguanides, meglitinides, oxadiazolidinediones,thizolidinediones, glucosidase inhibitors, glucagons antagonists such asthose disclosed in WO 99/01423, GLP-1 agonists, potassium channelopeners such as those disclosed in WO 98/26265 and WO 99/03861, insulinsensitizers, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors ofhepatic enzymes involved in stimulation of gluconeogensis and/orglycogenolysis, glucose uptake modulators, compounds modifying the lipidmetabolism such as antihyperlipidemic agents and antilipedimic agents asHMG CoA inhibitors (statins), compounds lowering food intake, PPAR andRXR agonists and agents acting on the ATP-dependent potassium channel ofthe B-cells.

In one embodiment of the invention the present compounds areadministered in combination with insulin. In further embodiments, thepresent compounds are administered in combination with a sulphonylureae.g., tolbutamide, glibenclamide, glipizide or glicazide, a biguanidee.g. metformin, a meglitinide e.g., repaglinide, a thizolidinedionee.g., troglitazone, ciglitazone, pioglitazone, rosiglitazone orcompounds disclosed in WO 97/41097 such as5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl-methyl]thiazolidine-2,4-dioneor a pharmaceutically acceptable salt thereof, preferably the potassiumsalt.

Furthermore, the present compounds may be administered in combinationwith the insulin sensitizers disclosed in WO 99/19313 such as (−)3-[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or apharmaceutically acceptable salts thereof, preferably the arginine salt.

In further embodiments, the present compounds are administered incombination with an a-glucosidase inhibitor e.g. miglitol or acarbose,an agent acting on the ATP-dependent potassium channel of the B-cellse.g. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide,nateglinide, an antihyperlipidemic agent or antilipidemic agent e.g.,cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol or dextrothyroxine,

In still further embodiments, the present compounds are administered incombination with more than one of the above-mentioned compounds e.g., incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, insulin, insulin and lovastatin, etc.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are B-blockers such as alprenolol, atenolol, timolot, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)intubitors such as benazepril, captopril, analapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, rimodipine, diltiazemand verapamil, and a-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 1995.

It should be understood that any-suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances are considered to be within the scope of the presentinvention.

The therapeutically effective amounts of the present compounds will be afunction of many variables, including the affinity of the inhibitor forthe tyrosine phosphatase, any residual activity exhibited by competitiveantagonists, the route of administration, the clinical condition of thepatient, and whether the inhibitor is to be used for the prophylaxis orfor the treatment of acute episodes.

In practicing the method of the present invention, the therapeuticpreparation will be administered to a patient in need of treatment at atherapeutically effective dosage level. The lowest effective dosagelevels can be determined experimentally by initiating treatment athigher dosage levels and reducing the dosage level until relief fromreaction is no longer obtained. Generally, therapeutic dosage levelswill range from about 0.01-100□g/kg of host body weight.

As discussed above, the present compounds can also administered inconjunction with other agents used in or proposed for the treatment ofindividual conditions as appropriate. However, when employed togetherwith the present compounds, these agents may be employed in lesserdosages than when used alone.

Where combinations are contemplated, it is not intended that the presentinvention be limited by the particular nature of the combination. Thepresent invention contemplates combinations as simple mixtures as wellas chemical hybrids. One example of the latter is where the presentcompound is covalently linked to a pharmaceutical compound, or where twoor more compounds are joined. For example, covalent binding of thedistinct chemical moieties can be accomplished by any one of manycommercially available cross-linking compounds.

In view of the therapeutic urgency attendant acute episodes, the presentcompounds may be intravenously infused or introduced immediately uponthe development of symptoms. However, prophylaxis is suitablyaccomplished by intramuscular or subcutaneous administration. In thisregard, the compositions are prepared as injectables, either as liquidsolutions or suspensions; solid forms suitable for solution in, orsuspension in, liquid prior to injection may also be prepared. Thesetherapeutic preparations can be administered to mammals for veterinaryuse, such as with domestic animals, and clinical use in humans in amanner similar to other therapeutic agents. In general, the dosagerequired for therapeutic efficacy will vary according to the type of useand mode of administration, as well as the particularized requirementsof individual hosts.

It is not intended that the present invention be limited by theparticular nature of the therapeutic preparation. For example, suchcompositions can be provided together with physiologically tolerableliquid, gel or solid carriers, diluents, adjuvants and excipients. Suchcompositions are typically prepared as sprays (e.g. intranasal aerosols)for topical use. However, they may also be prepared either as liquidsolutions or suspensions, or in solid forms including respirable andnonrespirable dry powders. Oral formulations (e.g. for gastrointestinaladministration) usually include such normally employed additives such asbinders, fillers, carriers, preservatives, stabilizing agents,emulsifiers, buffers and excipients as, for example, pharmaceuticalgrades of mannitol, lactose, starch, magnesium stearate, sodiumsaccharin, cellulose, magnesium carbonate, and the like. Thesecompositions take the form of solutions, suspensions, tablets, pills,capsules, sustained release formulations, or powders, and typicallycontain 1%-95% of active ingredient, preferably 2%-70%.

The compounds of the present invention are often mixed with diluents orexcipients that are physiologically tolerable and compatible. Suitablediluents and excipients are, for example, water, saline, dextrose,glycerol, or the like, and combinations thereof. In addition, if desiredthe compositions may contain minor amounts of auxiliary substances suchas wetting or emulsifying agents, stabilizing or pH buffering agents.

Additional formulations which are suitable for other modes ofadministration, such as topical administration, include salves,tinctures, creams, lotions, and, in some cases, suppositories. Forsalves and creams, traditional binders, carriers and excipients mayinclude, for example, polyalkylene glycols or triglycerides.

Determination of Activity

The compounds of the present invention are evaluated for biologicalactivity as inhibitors of PTP-1B using, for example, a Malachite Greenassay with pIRP as a substrate. The pIRP substrate includes aphosphotyrosine residue, and PTP-1B cleaves the phosphate group from thetyrosine, yielding the peptide and phosphate. The rate of the enzymaticreaction is determined by measuring the phosphate released during thereaction.

The reactants for the assay include 20 mM Tris-HCl, pH 7.4, 2 mM EDTA(ethylaminediamine tetraacetic acid) and 2 mM DTT (dithiothreitol) asthe assay buffer, and 1 mM pIRP in assay buffer (1 mg in 0.59 mL buffer)as the substrate stock. The Malachite Green solution is prepared byadding 30 μL of 1% Tween 20 to 1 mL of Malachite Green Solution A. Thestock of each compound to be tested is made up as 10 mM in DMSO(dimethylsulfoxide).

The compound to be tested is prepared as 1:5, 1:15.8, 1:50 and 1:158dilutions from stock in a total volume of 100 μM DMSO. The reactionmixtures are prepared in a 96-well microtiter plate as 27.5 μL assaybuffer, 3.5 μL of the diluted compound (to a final concentration of 100,32, 10 and 3.2 μM), 10 μL of the pIRP substrate solution (to a finalconcentration of 200 μM) and 10 μL PTPase in assay buffer. The reactantsare mixed well, the plate placed in a water bath at 30° C. and incubatedfor 3 minutes. The reaction is then terminated by adding 100 μL ofMalachite Green solution per well, color is allowed to develop for 15minutes, and the A₆₅₀ is measured by conventional means.

Unless otherwise indicated, this assay was used to determine activityfor the selected compounds whose activity is recorded in the Table.

Alternatively, a pNPP assay can be used to screen compounds for tyrosinephosphatase inhibitory activity as follows: A 5× stock of pNPP(p-nitrophenol phosphate) substrate is prepared as 50 mM pNPP in assaybuffer prepared as described above. Various tyrosine phosphatasesolutions can be prepared as follows:

-   -   PTP-1B (SBI purified, 1 mg/mL) as a 1:250 dilution (to a final        concentration of 4 μg/mL);    -   TC-PTP (NEB, 1000 units in 100 μL) as a 1:50 dilution (to a        final concentration of 2U/10 μL (4 μg/mL));    -   CD45 (Calbiochem, 20 μg, 400 units in 100 μL) as a 1:50 dilution        (to a final concentration of 0.8U/10 μL (4 μg/mL));    -   LAR (NEB, 1000 units in 200 μL) as a 1:75 dilution (to a final        concentration of 0.7U/10 μL (4 μg/mL)); and    -   PTP-β (UBI, #14-350, 10,000 units, 40 μg/571 μL) as a 1:17.5        dilution (to a final concentration of 10U/10 μL (4 μg/mL));

The compound to be tested is prepared as 1:16.7 and 1:50 dilutions fromstock in a total volume of 100 μM DMSO to give final concentrations of626 and 200 μM. The reaction mixtures are prepared in a 96-wellmicrotiter plate (on ice) as 55 μL assay buffer, 5 μL of the dilutedcompound (to a final concentration of 31.3 and 10 μM), 20 μL of the pNPPsubstrate solution (to a final concentration of 10 mM) and 20 μL PTeasein assay buffer. The reactants are mixed well, the plate placed in awater bath at 30° C. and incubated for 10 minutes. The reaction is thenterminated by adding 100 μL of 2M K₂CO₃ per well, and the absorbance ismeasured at 405 nm by conventional means.

Compounds which demonstrate inhibitory activity against tyrosinephosphatases can have application in the treatment of various diseases.For example, compounds which demonstrate inhibitory activity againstPTP-1B can find use in the treatment of diabetes. Compounds whichdemonstrate such activity against CD45 can find use in the treatment ofautoimmune diseases, inflammation, transplantation rejection reactions,and other diseases including arthritis, systemic lupus, Crohn's disease,inflammatory bowel disease, and other autoimmune disorders known tothose skilled in the art. Compounds which demonstrate such activityagainst TC-PTP can find use in the treatment of cancer, typically asantiangiogenic agents.

In the case of compounds which demonstrate inhibitory activity againstPTP-1B, one can test the compounds for blood glucose lowering effects indiabetic obese female ob/ob mice as follows: The mice will be of similarage and body weights and randomized into groups of ten mice. They havefree access to food and water during the experiment.

The compounds are administered by either gavage, subcutaneous,intravenous or intraperitoneal injections. Examples of typical doseranges for such evaluations are 0.1, 0.3, 1.0, 3.0, 10, 30, 100 mg perkg body weight. The blood glucose levels are measured twice beforeadministration of the compounds of the invention. After administrationof the compound, the blood glucose levels are measured at the followingtime points: 1, 2, 4, 6, and 8 hours. A positive response is definedeither as (i) a more than 25 percent reduction in blood glucose levelsin the group receiving the compound of the invention compared to thegroup receiving the vehicle at any time point or (ii) statisticallysignificant (i.e., p<0.05) reduction in the area under the blood glucosecurve during the whole period (i.e. 8 hrs) in the group treated with thecompounds of the invention compared to controls. Compounds that showpositive response can be used as development candidates for treatment ofhuman diseases such as diabetes and obesity.

The invention now being generally described, the same will be betterunderstood by reference to the following detailed examples, which areprovided for illustration and are not to be considered as limiting theinvention unless so specified. The structures of various of thedisclosed compounds will be found depicted in FIG. 1.

EXPERIMENTAL

In the experimental disclosure which follows, all weights are given ingrams (g), milligrams (mg), micrograms (μg), nanograms (ng), orpicograms (pg), all amounts are given in moles (mol), millimoles (mmol),micromoles (pmol), nanomoles (umol), picomoles (pmol), or femtomoles(fmol), all concentrations are given as percent by volume (%),proportion by volume (v:v), molar (M), millimolar (mM), micromolar (μM),nanomolar (nM), picomolar (pM), femtomolar (S), or normal (N), allvolumes are given in liters (L), milliliters (mL), or microliters (μL),and linear measurements are given in millimeters (mm), micrometers (μm),or nanometers (nm) and mp is melting point, unless otherwise indicated.

Example 1

N2-(3-bromophenyl)-5-(3-nitrophenyl)-1,3,4-thiadiazol-2-amine

To a solution of 3-bromophenyl isothiocyanate (6.5 g; 30.4 mmol) intoluene (150 mL) is added 3-nitrobenzhydrazide (5.0 g; 27.6 mmol) underargon. The reaction mixture is heated at reflux for two hours. Themixture is filtered while the toluene still is warm. The solid is washedwith warm toluene (3×50 mL) and dried to yieldN1-(3-bromophenyl)-2-(3-nitrobenzoyl) hydrazine-1-carbothioamide (10.7g; 98%) (mp. 163-165° C.). The product is used for the next step withoutfurther purification.

To a slurry mixture of the above carbothioamide (5.0 g; 12.7 mmol) intoluene (5 mL) at 0° C. is dropped con. H₂SO₄ (2.5 mL). The reactionmixture is stirred at room temperature (RT) for three hours. The tolueneis removed and ice-H₂O (50 mL) is added. The mixture is neutralized withNH₃.H₂O until pH 8 and filtered. The solid product is recrystallizedwith DMSO/MeOHEH₂O (3:5:10) to yieldN2-(3-bromophenyl)-5-(3-nitrophenyl)-1,3,4-thiadiazol-2-amine (4.5 g;94%). mp. 273-275° C. mass spec obsd M⁺376.88, M⁺-NO₂ 330.93, calcdexact mass 377.22 (C₁₄H₉BrN₄O₂S).

¹H NMR (DMSO-d₆) δ 7.23 (d, 1H), 7.34 (t, 1H), 7.52 (d, 1H), 7.82 (t,1H), 8.10 (s, 1H), 8.32 (t, 2H), 8.62 (s, 1H).

¹³C NMR (DMSO-d₆) δ 116.5, 119.9, 120.7, 122.0, 124.6, 124.8, 131.0,131.5, 133.1, 141.7, 148.3, 156.1.

Example 2

Methyl(3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)benzoate

A solution of the product from Procedure B (methyl3-(3-carbonylphenoxy)benzoate) (750 mg; 2.9 mmol) and(aminoamino)[(3,4-dichlorophenyl)amino]methane-1-thione (692 mg; 2.9mmol) in dry ethanol (8 mL) under argon is refluxed for two hours. Aftercooling to RT, the mixture was filtered and the solid washed by ethanol.The solid was suspension in dry ethanol (5 mL) and iron (III) chloridehexahydrate (1.546 g; 5.7 mmol) was added. The reaction mixture wasrefluxed for two hours, then cooled to RT. The solid was collected byfilter and washed by ethanol, then crystallized from ethylacetate/hexanes to yield the title compound (348 mg; 25%) of as a yellowsolid.

¹H NMR (300 MHz, d₆-DMSO): δ 10.92 (1H, s), 8.13 (1H, d, J=2.1 Hz), 7.79(1H, d, J=7.5 Hz), 7.68-7.55 (5H, m), 7.49 (1H, dd, J=8.7, 2.1 Hz), 7.43(1H, dd, J=8.1, 2.4 Hz), 7.21 (1H, d, J=8.1 Hz), 3.84 (3H, s).

Example 3

(3,4-dichlorophenyl)[5-(3,5-dinitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

To the product from Procedure D (59 mg; 0.25 mmol) was added3,5-dinitrobenzoyl chloride (50 mg; 0.25 mmol) in dichloromethane (˜1mL) at 0° C. (under argon). The reaction was allowed to rise to ambienttemperature (˜25° C.) and stirred for one hour. The solvent was removedby vacuum and the residue was subjected to silica gel flashchromatography (3% methanol in dichloromethane). The resultingintermediate was dissolved in toluene (˜1.5 mL) with con. H₂SO₄ (˜1 eq)and refluxed for two hours. Water and ammonium hydroxide were added (toneutralize) and the precipitate was collected by vacuum filtration.Recrystallization (ethanol/water) yielded the title compound (61%yield). mp 305-306.5° C.

Example 4

(4-{2[(3,4-dichlorophenyl)amino](1,3-thiazolfyl)}phenyl)diethylamine

To 3,4 dichlorobenzeneisothiocyanate (1 g; 4.8 mmol) in dry dioxane (15mL) at RT was added ammonium hydroxide (0.8 mL; 0.023 mmol) and ammoniumacetate (1.5 g; 19.5 mmol). The reaction mixture was refluxed for onehour. The solvent was removed under reduced pressure which affordedamino[(3,4-dichlorophenyl)amino]methane-1-thione (1.04 g; 98%) as whitesolid.

¹H NMR (CDCl₃) 9.88 (s, 1H); 7.91(s, 1H); 7.56 (d, 1H); 7.39 (d, 1H).

To a solution of amino[(3,4-dichlorophenyl)amino]methane-1-thione (100mg; 4.32 mmol) in dioxane (3 mL) at RT was addedalpha-bromo-4-(diethylamino)acetophenone (121 mg; 4.5 mmol). Thereaction mixture was stirred at RT for one hour and pyridine (0.4 mL;4.66 mmol) was added. After refluxing for five hours, the reactionmixture was concentrated under reduced pressure, quenched with water,and the resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water, then with brine, and dried over anhydroussodium sulfate. Concentration under reduced pressure afforded a crudeproduct which was purified by flash chromatography (50/50 Ethylacetate/Hexane) to yield the title compound (128 mg; 75%) as a purplesolid. The product had a HPLC retention time of 3.27 min (Column: C18, 5μm, 50×3 mm); Solvent A=(H₂O, 10% AcOH); solvent B=(Acetonitrile, 10%AcOH) and LC/SM M+=393.

¹H NMR (CDCl₃) 7.70-7.67(m, 2H); 7.37-7.26(m, 3H); 6.72-6.62(m, 3H);3.42-3.35(m, 4H); 1.21-1.16(m, 3H)

Example 5

(3-Bromophenyl)-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]-amine

A mixture of 3-nitrophenacylamine hydrochloride (620 mg; 2.8 mmol) andsodium bicarbonate (240 mg; 2.8 mmol) in H₂O (10 mL) was added to asolution of 3-bromophenylisothiocyanate (580 mg; 2.7 mmol) in acetone(23 mL). The resulting homogeneous solution was stirred at RT for 30minutes, after which it was partitioned between ethyl acetate and water.The ethyl acetate layer was dried over Na₂SO₄ and evaporated to drynessto yield N-(3-nitrophenacyl)-N′-(3-bromophenyl)-thiourea (400 mg; 38%).The thiourea was suspended in acetic anhydride (10 mL) containingpolyphosphoric acid (0.5 mL). After stirring for 12 hours at RT, themixture was poured over ice. The resulting solids were isolated viafiltration and triturated with 4/1 ethyl acetate/hexanes to yield puretitle compound as a yellow solid (150 mg; 38%); mp 228-231° C., MS m/z377.65 [MH⁺].

¹H NMR (300 MHz, DMSO-d₆) δ 7.17 (d, J=7.8 Hz, 1H), 7.30 (t, J=8.1 Hz,1H), 7.52 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.99 (d, J=8.4 Hz,2H), 8.09 (d, J=6.0 Hz, 2H), 8.31 (s, 1H), 10.72 (br s, 1H).

Example 6

(3-bromophenyl)[2-(3-nitrophenyl)(1,3-thiazol-5-yl)]amine

Without further purification, the intermediate from Procedure G (20 mg;0.053 mmol) was combined with2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione(Lawesson's reagent, 100 mg; 0.1 mmol) in pyridine (3 mL) and heated toreflux for three hours. The reaction mixture was diluted with ethylacetate, extracted 3× with 2N HCl, 1× with saturated aqueous potassiumcarbonate, and 1× with saturated aqueous sodium chloride. The organiclayer was dried with sodium sulfate, filtered, and stripped of solventin vacuo. The resulting solid was purified using silica chromatographyusing methylene chloride and 97:3 methylene chloride/methanol assolvents, yielding the title compound as an orange solid (12 mg; 60%yield). Mass Spectrum (electrospray, positive ion): calculated forMH+377, found 377; calculated for MNa+400, found 400.

Example 7

(3-(3-{5[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)benzoicacid)

The product from Example 2 (methyl3-(3-{5-[3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)benzoate(228 mg; 0.48 mmol) and LiOH (32 mg; 1.3 mmol) were suspension inTHF/MeOH/H₂O (2/3/9) (30 mL). The mixture was stirred overnight at RTand concentrated in vacuo. The residue was washed by ethyl acetate, then15% HCl aqueous solution was added until the pH was <7. The solid wascollected by filter and washed by water, then crystallized fromethanol/ethyl acetate/hexanes yields3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)benzoicacid (195 mg; 89%) as a white solid. mp 258-259° C.; MS (M+H)⁺458.2.

¹H NMR (300 MHz, d₆-DMSO): δ 13.21 (1H, br s), 10.94 (1H, s), 8.13 (1H,d, J=2.4 Hz), 7.70 (1H, d, J=8.4 Hz), 7.68-7.49 (7H, m), 7.40 (1H, dd,J=7.8, 2.1 Hz), 7.21 (1H, dd, J=8.1, 1.5 Hz).

Example 8

(3,4-dichlorophenyl){[4-(tert-butyl)phenyl]methyl}[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amineand

(1-(2-[aza(3,4-dichlorophenyl)methylenel-3-{[4(tert-butyl)phenyl]methyl}(1,3,4-thiadiazolin-5-yl)-3-ethoxybenzene)

To a solution of(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(120 mg; 0.33 mmol) in dry DMF (5 mL) was added a solution of potassiumtert-butoxide (0.33 mL; 1M; 0.33 mmol) in THF at RT under an argonatmosphere. After five minutes, 4-(tert-butyl)benzyl bromide (89 mg;0.39 mmol) was injected, and the solution was stirred overnight. The DMFwas evaporated (rotavap) under vacuum. The crude residue was purified byflash chromatography (ethyl acetate/hexanes, 100% hexanes to 1:4) to theisolation of the less polar isomer(1-(2-[aza(3,4-dichlorophenyl)methylene]-3-{[4-(tert-butyl)phenyl]methyl}(1,3,4-thiadiazolin-5-yl))-3-ethoxybenzene)(20 mg) in 12% yield R_(f)=0.60 (ethyl acetate/hexanes, 1:2).

¹H NMR (300 MHz, d₁-CDCl₃): δ 7.42-6.92 (11H, m), 5.29 (2H, s), 4.05(2H, q), 1.42 (3H, t), 1.32 (9H, s).

The other, more polar isomer,(3,4-dichlorophenyl){[4-(tert-butyl)phenyl]methyl}[5-(3-ethoxyphenyl)(1,3,4-thiadazol-2-yl)]amine(122 mg; 72%) was also isolated. R_(f)=0.48 (ethyl acetate/hexanes,1:2);

¹H NMR (300 MHz, d₁-CDCl₃): δ 7.49-6.92 (11H, m), 5.18 (2H, s), 4.07(2H, q), 1.43 (3H, t), 1.30 (9H, s).

Example 9

3-[3-(3-{5-[(3,4-Dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]propanoicacid

Trimethlsilyl diazomethane (15 mL; 30 mmol) was added to an ice coldsolution of 3-(3-hydroxyphenyl)propanoic acid (3.32 g; 20 mmol) inacetonitrile (40 mL). The mixture was stirred cold for 30 minutes andslowly brought to RT and continued to stir overnight. Acetic acid (1 mL)was added to quench the excess trimethylsilyl diazomethane. The reactionmixture was diluted with methanol (10 mL) and 1M hydrochloric acid (2mL), followed by rotoevaparation of the solvents. The residue waspurified over silica gel column. The compound was eluted withEtOAC/Hexanes (1/1) to yield methyl 3-(3-hydroxyphenyl)propanoate as anoil.

Yield: 3.2 g (90%). TLC (silica gel): R_(f)=0.8 (EtOAc/Hexane=1/1).

Methyl 3-[3-(3-formylphenoxy)phenyl]propanoate was prepared usingProcedure B from methyl 3-(3-methoxyphenyl)propanoate (2.7 g; 15 mmol),3-bromobenzaldehyde (1.75 mL; 15 mmol), copper oxide (2.4 g; 30 mmol)and potassium carbonate (4.14 g; 30 mmol) in pyridine as an oil. Yield:1.7 g (40%).

¹H NMR: (300 MHz, CDCl₃) 9.96δ (1H, s); 7.60δ (1H, d); 7.50δ (1H, t);7.45δ (1H, s); 7.25δ (2H, t); 7.01δ (1H, d) 6.88δ (1H, s); 6.86δ (1H,d); 3.66δ (3H, s); 2.95δ (2H, t); 2.63δ (2H, t).

Methyl3-(3-{3-[(1E)-2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)vinyl]phenoxy}phenyl)propanoate was prepared using the procedure inExample 2 from methyl 3-[3-(3-formylphenoxy)phenyl]propanoate (426 mg;1.5 mmol) and the product from Procedure D (354 mg; 1.5 mmol) to obtaina white solid. Yield: 450 mg (60%). Mass: M⁺: 502 (Calc.); 502 (Obsd.).

Ethyl3-[3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]propanoate was prepared using the procedure in Example 2 frommethyl3-(3-{3-[(1E)-2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)vinyl]phenoxy}phenyl)propanoate(400 mg; 0.8 mmol) and iron(III) chloride hexahydrate (432 mg; 1.6mmol). This product was used in the next reaction without furtherpurification. Yield: 250 mg (61%). Mass: M⁺: 514 (Calc.); 514 (Obsd).

3-[3-(3-{5-[(3,4-Dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]propanoic acid: The title compound was prepared using theprocedure for Example 7 from ethyl3-[3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]propanoate(150 mg; 0.29 mmol) and lithium hydroxide (24 mg; 1 mmol). Yield: 130 mg(91%). mp 194-196° C. Mass: M⁺: 486 (Calc.); 486 (Obsd.).

Example 10

2-[4-(Phenylmethoxy)phenyl]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))acetamide

A mixture of the product from Example 23 (202 mg; 0.6 mmol) and2-[4-(phenylmethoxy)phenyl]acetyl chloride (313 mg; 1.2 mmol), anddimethyl-4-pyridylamine (244 mg; 2.0 mmol) in CH₂Cl₂ (3 mL) was stirredat RT for 20 hours, then 1N HCl aqueous (10 mL) was added and stirred atRT for one hour. The aqueous layer was removed and the CH₂Cl₂ wasconcentrated. Water was added and filtration provided the title compound(107 mg; 32%), which was washed with water and then ethyl acetate: mp194-195° C.; Mass (M)⁺562 (Calc.); 562 (Obsd.).

Example 11

(3-bromophenyl)[5(3-{[3-trifluoromethyl)phenyl]methoxy]phenyl)(1,3,4-thiadiazol-2-yl)]amine

A mixture of 3-{5-[(3-bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenol(100 mg; 0.29 mmol) and 3-(bromomethyl)-1-(trifluoromethyl)benzene (82mg; 0.34 mmol) in dry DMF (5 mL) were stirred under argon at RT. Cesiumcarbonate (56 mg; 0.17 mmol) was added and this mixture stirredovernight. The reaction mixture was heated at 50° C. for one hour. TheDMF was evaporated (rotovap) under vacuum. The crude residue waspurified by flash chromatography (ethyl acetate/hexanes, 1:10 to 1:2) toyield the title compound((3-bromophenyl)[5-(3-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)(1,3,4-thiadiazol-2-yl)]amine)(92 mg; 63%) as white solid. mp 186-187° C. NMR: GE 300, QE+, LCMS:Finnigan, SSQ 7000 Mass Spectrometer

Example 12

3-[(3-{5[(3,4-Dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methylthio]propanoicacid

A mixture of3-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methan-1-ol(248 mg; 0.5 mmol) and 3-mercaptopropionic acid (531 mg; 5.0 mmol) intrifluoroacetic acid (1 mL) was stirred at RT for 20 hours. The solventand excess 3-mercaptopropionic acid was removed by rotovapor. Theresidue was purified by column chromatography on silica. Eluting withethyl acetate provided the title compound as a slightly brown solid (40mg; 16%): mp 140-141° C.; MS 583.9 (M).

Example 13

(3,4-dichlorophenyl)[5-(3-{ethoxy[3-trifluoromethyl)phenyl]methyl}phenyl)(1,3,4-tridiazole-2-y10]amine

Phosphorus tribromide (0.300 mL; 6.66 mmol) was added dropwise to asolution of((3-(1,3-dioxan-2-yl)phenyl)[3-trifluoromethyl)phenyl]methan-1-ol) (2.15g; 6.66 mmol) in ether (20 mL) while stirring under nitrogen at 0° C.After stirring for 2.5 hours at RT, the reaction was quenched by slowaddition of the reaction mixture onto ice (100 g). Following separationof layers, the aqueous layer was extracted with ether (3×75 mL). Theorganic layer was dried with magnesium sulfate, and evaporated underreduced pressure. The crude was purified using flash chromatography toyield (3-{bromo[trifluoromethyl)phenyl]methyl}phenyl)formaldehyde (1.42g; 4.15 mmol; 63%) as a colorless oil.

¹H NMR: 300 MHz; CDCl₃; 10.02 (s, 1H); 8.14-7.26(m, 8H); 6.32(s, 1H).

A solution of this aldehyde (290 mg; 0.85 mmol) and the product fromProcedure D (200 mg; 0.85 mmol), in ethanol (4 mL) was refluxed for 1.5hours, cooled to RT, and Iron (II) chloride hexahydrate was added to thereaction mixture. The reaction mixture was heated under reflux for twohours and then was cooled to RT. The solid was filtered and dried toyield the title compound (150 mg; 0.29 mmol). mp 200-205° C.; massspectrum M+=525.

¹H NMR: 300 MHz; CDCl₃; 7.93-7.26 (m, 12H); 5.46(s, 1H); 3.58-3.55(m,2H); 1.33-1.28(m, 3H).

Example 14

{5-[3-(3-(1H-1,2,3,4-tetraazol-5-yl)phenoxy)phenyl](1,3,4-thiadiazol-2-yl)}(3,4-dichlorophenyl)amine

To the product from Example 19 (120 mg; 0.28 mmol) in DMF (1.5 mL),under argon, was added ammonium chloride (42 mg; 0.82 mmol) and sodiumazide (53 mg; 0.82 mmol). The reaction was then heated at 115° C. for 96hours. TLC analysis revealed that a new product had formed in additionto unreacted starting material. The mixture was cooled to RT, dilutedwith water, extracted with dichloromethane, and dried over magnesiumsulfate. The crude oil was subjected to silica chromatography (100%dichloromethane; 5% methanol in dichloromethane) to yield pure tetrazole(45 mg), compound 2. Isolated yield 31%, uncorrected mp 227 to 229° C.(with decomposition).

Example 15

Ethyl2-[(3-{5-[(3,4-Dichlorophenyo)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methoxyl]acetate

A solution of(3-(1,3-dioxolan-2-yl)phenyl)[3-(trifluoromethyl)phenyl]methan-1-ol(3.23 g; 10 mmol) and sodium hydrade (260 mg; 11 mmol) in TBF (20 mL)was stirred under Argon at room temp for 1 hours. A solution oftert-butyl bromoacetate (1.95 g; 10 mmol) in TBF (10 mL) was added andthe resulting solution was refluxed for 24 hours. Water (10 mL) wasadded to quench the reaction. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×100 mL). The organiclayers were combined and dried over anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by column chromatography on silicagel. Eluting with ethyl acetate/hexanes (20:80) provide a colorlesssticky oil (2.4 g) as a mixture of tert-butyl2-{(3-(1,3-dioxolan-2-yl)phenyl)[3-(trifluoromethyl)phenyl]methoxy}acetate and(3-(1,3-dioxolan-2-yl)phenyl)[3-(trifluoromethyl)phenyl]methan-1-ol.

A sample of the product from the preceding paragraph (2.45 g) wascombined, without further purification, with pyridinium tosylate (500mg; 2.0 mmol) in acetone/water (4:1; 2 mL). The resulting solution wasrefluxed for two days. The solvent was removed and the residue wasextracted with ethyl acetate (3×30 mL). The organic layers were combinedand dried over anhydrous Na₂SO₄. The solvent was removed and the residuewas purified by flash column chromatography on silica gel. Eluting withethyl acetate/hexanes (20:80) provided a sticky oil (1.53 g) as amixture of tert-butyl2-{(3-carbonylphenyl)[3-(trifluromethyl)phenyl]methoxy} acetate and(3-{hydroxy[3-(trifluromethyl)phenyl]methyl}phenyl)formaldehyde.

A sample of the product from the preceding paragraph (1.52 g) wascombined, without further purification, with the product from ProcedureD (1.28 g; 5.4 mmol) in ethanol (20 mL). The resulting solution wasrefluxed for five hours. After cooling, the solution was concentratedand the residue was purified by flash column chromatography on silicagel. Eluting with ethyl acetate provided a brown solid (2.51 g) as amixture of tert-butyl2-({3-[2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}-amino)vinyl]phenyl}[3-(trifluoromethyl)phenyl]methoxy)acetateand{3-[2-aza-2-({[(3,4-dichlorophenyl)amino]-thioxomethyl}amino)vinyl]phenyl}[3-(tifluoromethyl)phenyl]methan-1-ol.

A sample of the product from the preceding paragraph (2.49 g) wascombined, without further purification, with iron (III) chloridehexahydrate (4.05 g; 15 mmol) in ethanol (20 mL). The resulting solutionwas refluxed for five hours. After cooling, the solution wasconcentrated and water (20 mL) was added. A brown sticky solid wasfiltered. This crude product was purified by flash column chromatographyon silica gel. Eluting with ethyl acetate/hexanes (1:1) provided a brownsolid (1.95 g), which is a mixture of3-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)-phenyl]methan-1-oland ethyl2-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methoxyl]acetate.This mixture (800 mg) was separated further by column chromatography onsilica gel. Eluting with ethyl acetate/hexanes (20:80) provided ethyl2-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methoxyl]acetate(200 mg): mp 135-136° C.; MS 582.0 (M); and also provided3-[(3-{5-[(3,4-dichlorophenyl)amino]-(1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methan-1-ol(250 mg): mp 191-192° C.; MS 495.8 (M).

Example 16

(3-methoxy-1-(6-(4-phenylphenyl)imidazolo(2,1-b)1,3,4-thiadiazolin-2-yl)benzene)

A mixture of anisic acid (9.88 g; 65 mmol), thiosemicarbozide (5.92 g;65 mmol) and phosphorous oxychloride (32.08 g; 210 mmol) was refluxedgently for 30 minutes. After cooling in an ice bath, a mixture of iceand water (60 mL) was added with stirring. The mixture was slowly warmedand refluxed for four hours. The reaction was cooled, neutralized with5M potassium hydroxide solution and the solid was filtered. The solidwas washed with water, then ether and dried to obtain5-(3-methoxyphenyl)-1,3,4-thiadiazole-2-ylamine. Yield: 8.10 g (60%).

¹H NMR: (300 MHz, DMSO-d6) 8.37δ (2H, b), 7.41δ (1H, t), 7.39δ (2H, m),7.07δ (1H, d), 3.82δ (3H, s).

A solution of 5-(3-methoxyphenyl)-1,3,4-thiadiazole-2-ylamine (1.8 g;8.7 mmol) and 2-bromo-4′-phenyl acetophenone (2.4 g; 8.7 mmol) wererefluxed for about 36 hours. The solid was filtered, washed with ethanoland hexane and dried to yield the title compound. Yield: 2.3 g (69%).

¹H NMR: (300 MHz, DMSO-d6) 8.84δ (1H, s), 7.99δ (2H, d), 7.74δ (4H, m),7.51δ (5H, m), 7.39δ (1H, d), 7.22δ (1H, m), 3.88δ (3H, s). Mass: MH+:384 (Calc.); 384 (Obsd.).

Example 17

N-{(1E)-2-aza-2-(3-bromophenyl)-1-[(4-phenylphenyl)methylthiolvinyl}[3-(trifluoromethyl)phenylcarboxamide

A solution of amino[(3-Bromophenyl)amino]methane-1-thione (100 mg; 0.43mmol) and 4-(bromomethyl-1-phenylbenzene (106 mg; 0.43 mmol) in dioxane(4 mL) was refluxed for four hours. Most of the solvent was evaporatedunder vacuum, and the residue was washed with ether (3×20 mL) to provide{[(3-Bromophenyl)amino][(4-phenylphenyl)methylthio]methyleneaminehydrobromide (160 mg; 78%) as a yellow solid. The intermediate was 95%pure by LC-MS (SSQ 7000) (retention time=3.26 min.; M+=398 free base.Column: Betasil C18 5 μm 50×3 mm.; Solvent A=water-0.1% AcOH;B=Acetonitrile −0.1% AcOH).

To a solution of{[(3-Bromophenyl)amino][(4-phenylphenyl)methylthio]methyleneaminehydrobromide (100 mg; 0.2 mmol) in dry pyridine (5 mL) was added3-(trifluoromethyl)benzoyl chloride at ambient temperature. Theresulting solution was refluxed for 15 minutes. The cold reactionmixture is poured into the water (10 mL). After filtration, the residuewas washed with water and tecrystallized from ethanol to yield the titlecompound. The product was 95% pure by LC-MS (SSQ 7000) (retentiontime=4.33 min.; M+=570 free base. Column: Betasil C18 5 μm 50×3 mm.;Solvent A=water-0.1% AcOH; B=Acetonitrile-0.1% AcOH). mp 220-225° C.from ethanol.

Example 18

[3-(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl))phenoxy)phenyl]-N-1,3-dioxolan-2-ylmethyl)carboxamide

To3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)benzoicacid (50 mg; 0.11 mmol) in DMF (1.5 mL) was added1,3-dioxolan-2-ylmethylamine (10 μL; 0.11 mmol). The mixture was warmedto dissolve the reactants and HATU (45 mg; 0.12 mmol) followed bytriethylamine (49 μL) were added and the mixture was stirred for fourhours. The solution was diluted with 0.5N aqueous HCl and extracted withdichloromethane (3×3 mL). The solvent was removed by high vacuum and theresulting residue was purified by silica gel chromatography (9/1Hex/EtOAc; 7/3 Hex/Oac). Yield: 27%, 15 mg., mp 200-203° C.

Example 19

3-(3-{5[3,4-dichlorophenylaminol-1,3,4-thiadiazol-2-yl}phenoxy)benzeneearbonitrile

3-hydroxybenzaldehyde and 3-bromobenzenecarbonitrile were combined as inProcedure B to yield 3-(3-carbonylphenoxy)benzenecarbonitrile. Yield:12% (isolated)

¹H NMR (300 MHz, CDCl₃): δ 10.00 (1H, s); δ 7.71 (1H, d, J=7.5 Hz); δ7.58 (1H, t, J=7.8 Hz); δ 7.50-7.42 (3H, m); δ 7.33-7.26 (3H, m).

3-(3-Formyl-phenoxy)-benzonitrile, 67 mmol, and[(3,4-dichloropheny)amino]hydrazinomethane-1-thione, 67 mmol, werecombined in ethanol and heated to reflux for two hours. The solution wascooled to room temperature and the precipitate was collected byfiltration, and then washed with hexane (3×). The white solid wasslurried in ethanol and 3 eq of Fe(III)Cl₃ was added. The slurry wasrefluxed for two hours, cooled and the crude product was collected byfiltration. The crude product was washed (3×) with water followed byhexane. The product was recrystallized from hot ethanol to give 1.4 g ofthe title compound. Yield 47%. mp 237-239° C. MS m/z 437.5 [M−H].

Example 20

3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiazol-2-yl)}3-(trifluoromethyl)phenyl]methan-1-ol

The product from Procedure E was refluxed for 18 hours with pyridiniump-toluenesulfonate in 4:1 acetone/water. After removal of acetone invacuo, water and ethyl acetate were added. The organic layer was washed3 times with water, then with saturated sodium chloride, dried oversodium sulfate, filtered and stripped of solvent in vacuo to yield(3-{hydroxy[3-(trifluoromethyl)phenyl]methyl}phenyl)formaldehyde.

A solution of [(3,4-dichlorophenyl)amino]hydrzinomethane-1-thione (200mg; 0.85 mmol), and(3-{hydroxy[3-(trifluoromethyl)phenyl]methyl}phenyl)formaldehyde (290mg; 0.85 mmol) in ethanol (4 mL) was refluxed for 1.5 hours, cooled toRT, and Iron (III) chloride hexahydrate was added to the reactionmixture. And the reaction mixture was heated under reflux for two hours.The reaction was cooled to RT, and the ethanol was removed under reducedpressure. The crude was purified by flash chromatography to yield thetitle compound (25 mg; 0.05 mmol, 16%)

Example 21

(2E)-3-{4[5-((3-[(2-Phenylphenyl)methylthio]phenylamino)(1,3,4-thiadiazol-2yl)]phenyl}prop-2-enoic acid

(2E)-3-[4-((1E)-2-Aza-2-{[({3-[(2-Phenylphenyl)methylthio]phenyl}amino)thioxomethyl]amino}vinyl)phenyl]prop-2-enoic acid was prepared using theprocedure for Example 2 fromhydrazino(1{3-[(2-phenylphenyl)methylthio]phenyl}amino)methane-1-thione(183 mg; 0.5 mmol) and 4-formylcinnamic acid (88 mg; 0.5 mmol) to obtaina yellow solid.

Yield: 197 mg (75%). TLC (silica gel): R_(f)=0.43.

Ethyl(2E)-3-{4-[5-({3-[(2-phenylphenyl)methylthio]phenyl}amino)(1,3,4-thiadiazol-2-yl)]phenyl}prop-2-enoatewas prepared using the procedure for Example 2 from(2E)-3-[4-(1E)-2-aza-2-{[({3-[(2-phenylphenyl)methylthio]phenyl}amino)thioxomethyl]amino}vinyl)phenyl]prop-2-enoicacid (130.9 mg; 0.25 mmol) and iron(III) chloride hexahydrate (203 mg;0.75 mmol) to obtain a yellow solid. Yield: 88 mg (64%). TLC (silicagel): R_(f)=0.56.

The title compound was prepared using the procedure for Example 7 fromethyl (2E)-3-{4-[5-({3-[(2-phenylphenyl)methylthio]phenyl}amino)(1,3,4-thiadiazol-2-yl)]phenyl}prop-2-enoate (70 mg; 0.13 mmol) andlithium hydroxide (24 mg; 1 mmol). Yield: 56 mg (84%). mp 255-257° C.Mass (APCI): (MH)⁺: 522 (Calc.); 522 (Obsd.).

Example 22

[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](3-bromophenyl)amine

To a solution of amino[(3-bromophenyl)amino]methane-1-thione (10 mg;4.32 mmol) in dioxane (3 mL) at RT was added1-(3,4-dichlorophenyl)-2-bromoethan-1-one (120 mg; 4.5 mmol). Thereaction mixture stirred at RT for one hour and pyridine (0.4 mL; 4.66mmole) was added. After refluxing for five hours, the reaction mixturewas concentrated under reduced pressure, quenched with water, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water, with brine, and dried over anhydrous sodiumsulfate. Concentration under reduced pressure afforded a crude productthat was purified by flash chromatography (50/50 Ethyl acetate/Hexane)to yield the title compound (135 mg; 78%) as a liquid. The product had aHPLC retention time of 3.90 minutes (Column: C18, 5 μm, 50×3 mm);Solvent A=(H2O, 10% AcOH); solvent B=(Acetonitrile, 10% AcOH) and LC/SM(SSQ-7000) M+=400.

Example 23

5-{3-[3-(trifluoromethyl)phenoxy]phenyl})-1,3,4-thiadiazole-2-ylamine

The reactions described in Example 2 were repeated, usingaminohydrazinomethane-1-thione (1.82 g; 20.0 mmol) and3-[3-(trifluoromethyl)phenoxy]benzaldehyde (5.32 g; 20.0 mmol) to yield[(1-aza-2-{3-[3-(trifluoromethyl)phenoxy]phenyl}vinyl)amino]aminomethane-1-thione(6.43 g; 95%) in the first step.

In the second step,[(1-aza-2-{3-[3-(trifluoromethyl)phenoxy]phenyl}vinyl)amino]aminomethane-1-thione(6.35 g; 18.7 mmol) and iron (III) chloride hexahydrate (12.16 g; 45.0mmol) were used to yield the title compound (2.42 g; 38%). mp 214-215°C.; Mass (M)⁺337 (Calc.); 337 (Obsd.).

Example 24

4-{2-[(3-bromophenyl)amino]-1,3-thiazol-4-yl}phenyl benzoate

To a solution of amino[(3-bromophenyl)amino]methane-1-thione (100 mg;4.32 mmol) in dioxane (3 mL) at RT was added 4-(2-bromoacetyl)phenylbenzoate (143 mg; 4.5 mmol). The reaction mixture stirred at RT for onehour and pyridine (0.4 mL; 4.66 mmole) was added. After refluxing forfive hours the reaction mixture was concentrated under reduced pressure,quenched with water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, with brine, and driedover anhydrous sodium sulfate. Concentration under reduced pressureafforded a crude product that was purified by flash chromatography(50/50 Ethyl acetate/Hexane) to yield the title compound (146 mg; 75%)as a white solid. mp from ethyl acetate: 168-170° C. The product had aHPLC retention time of 3.57 min (Column: C18, 5 μm, 50×3 mm); SolventA=(H₂O, 10% AcOH); solvent B (Acetonitrile, 10% AcOH) and LC/SM(SSQ-7000) M+=452.

Example 25

3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-3-yl)}phenyl3-(trifluoromethyl)phenyl ketone

To the product from Procedure E (500 mg; 1.5 mmol) and celite (11.0 g)in dichloromethane (4 mL) was add pyridinium chlorochromate (970 mg; 4.5mmol). The mixture was stirred for two hours, filtered, and the filtercake was rinsed with additional dichloromethane and the filtrateconcentrated in vacuo to an oily residue. The residue was subjected tosilica gel chromatography (1/9 ethyl acetate/hexane) to yield3-(1,3-dioxolan-2-yl)phenyl 3-(trifluoromethyl)phenyl ketone (442 mg;91%).

This intermediate was hydrolyzed to the3-{[3-(trifiuoromethyl)phenyl]carbonyl}benzaldehyde by stirring in 1NHCl/Dioxane (1/1) for two hours at 25° C. The aldehyde (154 mg, 0.56mmol) and the product from Procedure D (132 mg; 0.56 mmol) were thencombined as in Example 2 and recrystallized from ethanol to yield thetitle compound.

Yield 175 mg (63%). mp (uncorrected): 216-217° C.

Example 26

N-{(1Z-2-aza-2-3,4-dichlorophenyl)-1-[(4-(1,2,3-thiadiazol-4-yl)phenyl)methylthio]vinyl}[3-(trifluoromethyl)phenyl]carboxamide

A solution of amino[(3,4-dichlorophenyl)amino]methane-1-thione (145 mg;0.65 mmol) and 4-[4-(bromomethyl)phenyl]-1,2,3-thiadiazole in dioxane (4mL) was refluxed for four hours. Most of the solvent was evaporatedunder vacuum, and the residue was washed with ether (3×20 mL) to providethe HBr salt of{amino[(4-(1,2,3-thiadiazol-4-yl)phenyl)methylthio]methyl}(3,4-dichlorophenyl)amine(248 mg; 80%) as a yellow solid.

¹HNMR (300 MHz, CDCl₃); 11.31(s, 1H); 8.69(s, 1H); 8.08-8.05(d, J=9 Hz,1H); 7.59-7.20 (m, 7H); 4.68 (s, 2H).

To a solution of this salt (116 mg; 0.23 mmol) in dry pyridine (5 mL)was added 3-(trifluoromethyl)benzoyl chloride at RT. The resultingsolution was refluxed for 15 minutes. The cold reaction mixture ispoured into the water (10 mL). The precipitate is filtered, washed withwater, and recrystallized from ethanol to yield the title compound as awhite solid. Mass spec (APCI): M+=566: mp 150-155° C.

Example 27

1-(4-{[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]amino}phenyl)ethan-1-one

The title compound was synthesized from 3-nitro-benzenecarbohyrazide(181 mg; 1 mmol) and 4-acetylbenzenisothiocyanate (197 mg; 1.1 mmol) bythe procedure of Example 1. recrystallized from ethanol/water. Yield:38% (isolated) Mass spec: (MH⁺) 341.1 (NuMega)

Example 28

Ethyl2-(3-{5-[(3-bromophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)acetate

The title compound was synthesized from[(3-bromophenyl)amino]hydrazinometlhane-1-thione (80 mg; 0.47 mmol) and2-(3-carbonylphenoxy) acetic acid (10 mg; 0.43 mmol) by the procedure ofExample 2. Yield: 62% (isolated) mp 175° C. (uncorrected) from ethylacetate/hexane.

Example 29

(3,4-dichlorophenyl)[5-(3,5-dinitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was synthesized from 3,5-dinitrobenzoyl chloride (50mg; 0.25 mmol) and the product from Procedure D (59 mg; 0.25 mmol) bythe procedure of Example 3. mp 305-306.5° C. (uncorrected) from ethanol.Yield: 61% (isolated)

Example 30

[5-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-phenoxyphenyl)amine

The title compound was synthesized fromamino[(4-phenoxyhenyl)amino]methane-1-thione (228 mg; 0.9 mmol) and2-bromo-1-(4-nitrophenyl)ethan-1-one (240 mg; 1.2 mmol) by the procedureof Example 4. Yield: 45% (isolated) mp 191-196° C. (uncorrected) fromethyl acetate/hexane

Example 31

Methyl3-(aza(5-(3-ethoxyphenyl]-3-[4-phenylphenyl)methyl(1,3,4-thiadiazolin-2-ylidene)}methyl)benzoate

The title compound was synthesized frommethyl-3{[5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl]amino}benzoate and4-(bromomethyl)-1-phenylbenzene by the procedure in Example 8 andpurified using silica gel chromatography as the less polar of the twoisomers. Mass: (MH+)⁺552.07 SBI APCI+Q1 ms

Example 32

Ethyl 2-[(1Z &1E)-1-aza-2-(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-3-yl)}phenyl)-2-[3-(trifluoromethyp)phenyl]vinyloxy]acetate

To the product from Example 25 (168 mg; 0.34 mmol) was addedcarboxymethoxylamine hydrochloride (43 mg; 0.34 mmol) in ethanol. Thereaction mixture was refluxed for six hours, then allowed to cool to 0°C. The precipitate was collected and recrystallized from ethanol toyield the product (75 mg; a mixture of cis and trans). Yield 37%(isolated). mp 170-179° C.

Example 33

1-(4-{[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]amino}phenyl)ethan-1-one

The title compound was synthesized from 4-acetylphenyl isothiocyanateand 3-nitrobenzoylhydrazide using the procedure in Example 1. Yield: 38%(isolated) Mass: (MH+)⁺341.1

Example 34

[5-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-phenoxyphenyl)amine

4-phenoxybenzenisothiocyanate (1.0 g; 4.4 mmol) and 0.5M ammonia (30 mL;15 mmol) in dioxane were combined as in Example 4 to yield(amino[(4-phenoxyphenyl)amino]methane-1-thione) in 83% yield. Withoutpurification, this intermediate was combined with4-nitrophenyl-2′-bromoacetophenone as in Example 4 to yield the titlecompound in 45% yield. mp 191-196° C. (uncorrected); Yield: 45%(isolated).

Example 35

3-{2-[Aza(3,4-dichlorophenyl)methylene]-3-methyl(1,3,4-thiadiazolin-5-yl))-1-[3-(trifluoromethyl)phenoxy]benzene

and

(3,4-Dichlorophenyl)methyl(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amine

The reactions described in Example 8 were repeated, but using(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amine(241 mg; 0.5 mmol), potassium t-butoxide (0.55 mL; 0.55 mmol; 1M in THF)and of iodomethane (0.12 mL; 2 mmol) to yield3-{2-[Aza(3,4-dichlorophenyl)methylene]-3-methyl(1,3,4-thiadiazolin-5-yl)}-1-13-(trifiuoromethyl)phenoxy]benzene(41 mg; 17%, the less polar of the two isomers) with the followingphysical properties: mp 78-79° C.; MS m/z 496 (M⁺) (LC/MS SSQ.7000).

The more polar isomer,(3,4-Dichlorophenyl)methyl(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amine,was isolated in a yield of 20 mg (8%), with the following physicalproperties: MS m/z 496 (M⁺) (LC/MS SSQ.7000);

¹HNMR (300 MHz, CDCl₃) 3.63 (s, 3H), 7.07 (d, J=8.7 Hz, 1H), 7.19 (d,J=8.1 Hz, 1H), 7.26-7.53 (m, 9H).

Example 36

(3-Bromophenyl){5-[(2-nitrophenoxy)methyl](1,3,4-thiadiazol-2-yl)}amine2-(2-nitrophenoxy)acetohydrazide (211 mg; 1 mmol) and 3-bromophenylisothiocyanate (235 mg; 1.1 mmol) were combined as in Example 1 to formthe title compound (193 mg; 81% yield): mp 184-185° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 5.64 (s, 2H), 7.19 (d, J=6.0 Hz, 2H), 7.31(t, J=6.9 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.70(t, J=6.6 Hz, 1H), 7.92 (d, J=6.9 Hz, 1H), 8.05 (s, 1H), 10.67 (s, 1H);MS m/z 407 (MN; R_(f) 0.65 (EtOAc, silica).

Example 37

3-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)benzoicacid

3-[(hydrazinothioxomethyl)amino]benzoic acid was prepared usingProcedure F from 3-carboxyphenyl isothiocyanate (896 mg; 5 mmol) andhydrazine hydrate (485 μL; 10 mmol) and was used for next reactionwithout further purification.

¹H NMR: (300 MHz, DMSO-d₆) 9.11 δ (1H, b); 8.07 δ (1H, s); 7.73 δ (1H,d); 6.23 δ (1H, d); 7.23 δ (1H, t); 7.00 δ (2H, b); 4.84 δ (1H, b).

The title compound was prepared using the procedure for Example 2 from3-[(hydrazinothioxomethyl)amino]benzoic acid (845 mg; 4 mmol) and3,5-dibenzyloxy benzaldehyde (1.27 g; 4 mmol). Yield: 152 mg (10%).Mass: (MH)⁺: 510

Example 38

1-{6-[3-(2,4-Dichlorophenyl)isoxazol-5-yl]imidazolo[2,1-b]1,3,4-thiadiazolin-2-yl}-3-methoxybenzene

The title compound was prepared as in Example 16 from 5-(3-methoxyphenyl)-1,3,4-thiadiazole-2-ylamine (103 mg; 0.5 mmol) and5-(bromoacetyl)-3-(2,4-dichlorophenyl)isoxazole (168 mg; 0.5 mmol).Yield: 75 mg (34%). mp 195-198° C. Mass: (M)⁺: 443 (Calc.); 443 (Obsd.).

Example 39

2-(3-Nitrophenyl)-6-(4-phenylphenyl)imidazolo[2,1-b]1,3,4-thiadiazoline5-(3-Nitrophenyl)-1,3,4-thiadiazole-2-ylamine was prepared using theprocedure for Example 16 from 3-nitro benzoic acid (5.01 g; 30 mmol) andthiosemicarbozide (2.73 g; 30 mmol) and phosphorous oxychloride (9 mL).Yield: 3.29 g (50%). mp 205-206° C. Mass: (M+2H)⁺: 224 (Calc.), 224(Obsd.).

2-(3-Nitrophenyl)-6-(4-phenylphenyl)imidazolo[2,1-b]1,3,4-thiadiazoline:The title compound was prepared using the procedure of Example 16 using5-(3-nitrophenyl)-1,3,4-thiadiazole-2-ylamine (111 mg; 0.5 mmol) and2-bromo-4′-phenyl acetophenone (138 mg; 0.5 mmol). Yield: 75 mg (19%).mp 263-265° C. Mass: (MH)⁺: 399 (Calc.); 399 (Obsd.).

Example 40

6-(2H,3H,4EI-Benzo[b]1,4-dioxepan-7-yl)-2-(3-nitrophenyl)imidazolo[2,1-b]1,3,4-thiadiazoline

The title compound was prepared using the procedure of Example 16 using5-(3-nitrophenyl)-1,3,4-thiadiazole-2-ylamine (111 mg; 0.5 mmol) and3,4-(Trimethylenedioxy)phenacyl bromide (136 mg; 0.5 mmol). Yield: 75 mg(18%). mp 227-230° C. Mass: (M⁺: 395 (Calc.); 395 (Obsd.).

Example 41

{3-[(4-Methoxyphenyl)methylthio]phenyl}[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

3-(4-Methoxy phenylmethylthio)phenylamine: The title compound wasprepared from 4-(chloromethyl)-1-methoxybenzene (4.7 g; 30 mmol) and3-amino thiophenol (3.75 g; 30 mmol) using Procedure A. The solid waspurified using a silica gel column and the title compound was elutedwith 20% EtOAc/hexanes. Yield: 4.5 g (61%).

3-[(4-Methoxyphenyl)methylthio]benzenisothiocyanate was prepared usingProcedure C from 3-(4-methoxy phenylmethylthio)phenylamine (1.84 g; 7.5mmol) and thiophosgene (1.14 mL; 15 mmol) to obtain slightly purplesolid. Yield: 2.0 g (93%).

Hydrazino({3-[(4-methoxyphenyl)methylthio]phenyl}amino)methane-1-thionewas prepared from 3-(phenylmethylthio) benzenisothiocyanate (290 mg; 1mmol) and hydrazine hydrate (0.1 mL; 2 mmol) using Procedure D. Yield:275 mg (86%).

[(1E)-1-Aza-2-(3-nitrophenyl)vinyl]amino}({3-[(4-methoxyphenyl)methylthio]phenyl}amino)methane-1-thionewas prepared from hydrazino({3-[(4-methoxyphenyl)methylthio]phenyl}amino)methane-1-thione (240 mg; 0.75 mmol) and3-nitrobenzaldehyde (113 mg; 0.75 mmol) as in Example 2. Yield: 275 mg(81%). TLC (silica gel): R_(f)=0.9 (EtOAc/Hexane-1/1).

The title compound was prepared as in Example 2 from{[(1E)-1-aza-2-(3-nitrophenyl)vinyl]amino}({3-[(4-methoxyphenyl)methylthio]phenyl}amino)methane-1-thione(226 mg; 0.5 mmol) and iron (III) chloride hexahydrate (405 mg; 1.5mmol). Yield: 176 mg, (78%). mp 208-209° C. Mass spectrum(electrospray): NH)⁺: 451 (Calc.); 451 (Obsd.).

Example 42

[5-(3-Ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]{3-[(4-phenylphenyl)methylthio]phenyl}amine

3-[(4-Phenylphenyl)methylthio]phenylamine: The title compound wasprepared using Procedure A from 3-aminothiophenol (0.4 mL; 3.5 mmol) and1-(chloromethyl)₄-phenylbenzene (750 mg; 3.5 mmol) as a white solid.Yield: 970 mg (95%). TLC (silica gel): R_(f)=0.4 (EtOAc/Hexane=1/4).

3-[(4-Phenylphenyl)methylthio]benzenisothiocyanate was prepared usingProcedure C from 3-[(4-phenylphenyl)methylthio]phenylamine (950 mg; 3.25mmol) and thiophosgene (0.49 mL; 6.5 mmol). Yield: 910 mg (84%). TLC(silica gel): Rf=0.9 (EtOAc/Hexane=1/4).

Hydrazino({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thionewas prepared using Procedure D from3-[(4-phenylphenyl)methylthio]benzenisothiocyanate (900 mg; 2.7 mmol)and hydrazine hydrate (0.27 mg; 5.4 mmol) as a white solid. Yield: 750mg (76%).

{[(1E)-1-Aza-2-(3-ethoxyphenyl)vinyl]amino}({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thione:The title compound was prepared as in Example 2 fromhydrazino({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thione(274 mg; 0.75 mmol) and 3-ethoxybenzaldehyde (113 mg; 0.75 mmol) toobtain a white solid. Yield: 320 mg (85%).

The title compound was prepared using the procedure for Example 2 from{[(1E)-1-aza-2-(3-methoxyphenyl)vinyl]amino}({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thione (242 mg; 0.5 mmol) and iron(III) chloride hexahydrate(405 mg, 1.5 mmol). Yield: 172 mg (69%). mp 215-217° C. Mass: (MN)⁺: 496(Calc.); 496 (Obsd.). AA

Example 43

[5-3-Nitrophenyl)(1,3,4-thiadiazol-2-yl)]{3-[(4-phenylphenyl)methylthio]phenyl}amine

{[(1E)-1-Aza-2-(3-nitrophenyl)vinyl]amino}({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thionewas prepared using the procedure in Example 2 fromhydrazino({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thione(183 mg; 0.5 mmol) and 3-nitrobenzaldehyde (76 mg; 0.5 mmol) as a whitesolid. Yield: 210 mg (84%).

The title compound was prepared as in Example 2 from{[(1E)-1-aza-2-(3-nitrophenyl)vinyl]amino}({3-[(4-phenylphenyl)methylthio]phenyl}amino)methane-1-thione (200 mg; 0.4 mmol) and iron(III) chloride hexahydrate(324 mg; 1.2 mmol). Yield: 90 mg (45%). mp 229-231° C. Mass: (MH)⁺: 497(Calc.); 497 (Obsd.).

Example 44

[5-(3-Methylphenyl)(1,3,4-thiadiazol-2-yl)](2,4,5-trichlorophenyl)amine

(3-Methylphenyl)-N-({thioxo[(2,4,5-trichlorophenyl)amino]methyl}amino)carboxamide:The title compound was prepared using the procedure for Example 1 from3-toluic hydrazide (100 mg; 0.67 mmol) and 2,4,5-trichlorophenylisothiocyanate (160 mg; 0.67 mmol). Yield: 39.2 mg (15%). TLC (silicagel): R_(f)=0.17.

The title compound was prepared using the procedure for Example 1 from(3-methylphenyl)-N-({thioxo[(2,4,5-trichlorophenyl)amino]methyl}amino)carboxamide(79 mg; 0.2 mmol) and sulfuric acid (6 drops). Yield: 16 mg (21.5%). mp229-231° C. Mass (electrospray): (MH)⁺: 497 (Calc.); 497 (Obsd.).

Example 45

{5[3,5-Bis(phenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}[3-(3-phenylpropylthio)phenyl]amine

3-(3-Phenylpropylthio)phenylamine was prepared from 3-amino thiophenol(10 mmol, 1.06 mL) and (3-bromopropyl)benzene (1.52 mL; 10 mmol) usingProcedure A. The yellow liquid was purified using a silica gel columnand the title compound was eluted with 40% hexanes/ethylacetate. Yield:1.7 mL (74%).

3-(3-Phenylpropylthio)benzenisothiocyanate was prepared using ProcedureC from 3-(3-phenylpropylthio)phenylamine (1.8 g; 7.4 mmol) andthiophosgene (1.12 mL; 14.8 mmol) to obtain a brown liquid. Yield: 2.3 g(100%).

Hydrazino {[3-(3-phenylpropylthio)phenyl]amino}methane-1-thione: Thetitle compound was prepared using Procedure F from3-(3-phenylpropylthio)benzenisothiocyanate (2.3 g; 8 mmol) and hydrazinehydrate (0.4 mL; 16 mmol) to obtain a white solid. Yield: 2.11 g (83%).TLC (silica gel): R_(f)0.25.

({(1E)-1-Aza-2-[3,5-bis(phenylmethoxy)phenyl]vinyl}amino){[3-(3-phenylpropylthio)phenyl]amino}methane-1-thione was prepared using the procedure forExample 2 fromhydrazino{[3-(3-phenylpropylthio)phenyl]amino}methane-1-thione (159 mg;0.5 mmol) and 3,5-dibenzyloxybenzaldehyde (159 mg; 0.5 mmol). Yield: 290mg (94%). TLC (silica gel): R_(f)=0.84.

5-[3,5-bis(phenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}[3-(3-phenylpropylthio)phenyl]amine: The title compound was prepared as in Example 2 from({(1E)-1-aza-2-[3,5-bis(phenylmaethoxy)phenyl]viny}amino){[3-(3-phenylpropylthio)phenyl]amino}methane-1-thione (154 mg; 0.25mmol) and iron(III) chloride hexahydrate (202 mg; 0.75 mmol). Yield: 124mg (81%). mp 160-162° C. Mass: (W)⁺: 616 (Calc.); 616 (Obsd.). AA

Example 46

{5-[3,5-Bisphenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}{3-[(2-phenylphenyl)methylthio]phenyl}amine

3-[(2-Phenylphenyl)methylthio]phenylamine was prepared from 3-aminothiophenol (10 mmol, 1.06 mL) and 2-phenylbenzyl bromide (1.83 mL; 10mmol) using Procedure A. The yellow liquid was purified using a silicagel column and the title compound was eluted with 40%hexanes/ethylacetate. Yield: 1.8 mL (62%). TLC (silica gel): R_(f)=0.72

3-[(2-Phenylphenyl)methylthio]benzenisothiocyanate was prepared usingProcedure C from 3-[(2-phenylphenyl)methylthio]phenylamine (1.8 g; 6mmol) and thiophosgene (0.91 mL; 12 mmol) to obtain a brown liquid.Yield: 2.2 g (90%). TLC (silica gel): R_(f)0.69.

Hydrazino({3-[(2-Phenylphenyl)methylthio]phenyl}amino)methane-1-thionewas prepared using Procedure F from3-[(2-phenylphenyl)methylthio]benzenisothiocyanate (2.2 g, 6.6 mmol) andhydrazine hydrate (0.33 mL; 13.2 mmol) to obtain a white solid. Yield:1.91 g (79%). TLC (silica gel): R_(f)=0.28.

({(1E)-1-Aza-2-[3,5-bis(phenylmethoxy)phenyl]vinyl}amino)({3-[(2-phenylphenyl)methylthio]phenyl}amino)methane-1-thione: The title compound wasprepared using the procedure for Example 2 fromhydrazino({3-[(2-phenylphenyl)methylthio]phenyl}amino)methane-1-thione(183 mg; 0.5 mmol) and 3,5-dibenzyloxybenzaldehyde (159 mg; 0.5 mmol) toobtain a white solid. Yield: 132 mg (40%). TLC (silica gel): R_(f)=0.84

The title compound was prepared using the procedure for Example 2 from({(1E)-1-aza-2-[3,5-bis(phenylmethoxy)phenyl]vinyl}amino)({3-[(2-phenylphenyl)methylthio]phenyl}amino)methane-1-thione (120 mg; 0.18 mmol) andiron(III) chloride hexahydrate (146 mg; 0.54 mmol). Yield: 85 mg (71%).mp 128-130° C. Mass (electrospray): (MH)⁺: 664 (Calc.); 664 (Obsd.)⁺.

Example 47

{3-[(2-Phenylphenyl)methylthio]phenyl}{5-[2-(trifluoromethyl)phenyl](1,3,4-thiadiazol-2-yl)}amine

({(1E)-1-Aza-2-[2-(trifluoromethyl)phenyl]vinyl}amino)({3-[(2-phenylphenyl).methylthio]phenyl}amino)methane-1-thione was prepared using theprocedure for Example 2 fromhydrazino({3-[(2-phenylphenyl)methylthio]phenyl}amino)methane-1-thione(183 mg; 0.5 mmol) and 2-(trifluoromethyl) benzaldehyde (0.7 mL; 0.5mmol) to obtain a white solid.

Yield: 104 mg (40%). TLC (silica gel): R_(f)=0.84.

{3-[(2-Phenylphenyl)methylthio]phenyl}{5-[2-(trifluoromethyl)phenyl](1,3,4-thiadiazol-2-yl)}aminewas prepared using the procedure for Example 2 from({(1E)-1-aza-2-[2-(trifluoromethyl)phenyl]vinyl}amino)({3-[(2-phenylphenyl)methylthio]phenyl}amino)methane-1-thione (94 mg; 0.18 mmol) and iron(III) chloride hexahydrate(146 mg; 0.54 mmol).

Yield: 50 mg (53%). mp 73-75° C. Mass (electrospray): (MH)⁺: 520.

Example 48

[5-(3-Nitrophenyl)(1,3,4-thiadiazol-2-yl)][3-(3-phenylpropylthio)phenyl]amine

The intermediate{[(1E)-1-Aza-2-(3-nitrophenyl)vinyl]amino}{[3-(3-phenylpropylthio)phenyl]amino}methane-1-thione was prepared using the procedure forExample 2 usinghydrazino{[3-(3-phenylpropylthio)phenyl]amino}methane-1-thione (159 mg;0.5 mmol) and 3-nitrobenzaldehyde (76 mg; 0.5 mmol) as a yellow solid.Yield: 194 mg (86%). TLC (silica gel): R_(f)=0.78.

The title compound was prepared using the procedure for Example 2 from{[(1E)-1-aza-2-(3-nitrophenyl)vinyl]amino}{[3{3-phenylpropylthio)phenyl]amino}methane-1-thione(112.6 mg; 0.25 mmol) and iron(III) chloride hexahydrate (203 mg; 0.75mmol). Yield: 945 mg (85%). mp 169-171° C. Mass: (MH)⁺: 449 (Calc.); 449(Obsd.). AA

Example 49

4-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)benzoleacid

Methyl 4-[hydrazinothioxomethyl)amino]benzoate was prepared usingProcedure F from 4-methoxycarbonylphenyl isothiocyanate (193 mg; 1 mmol)and hydrazine hydrate (0.1 mL; 2 mmol) as a white solid. Yield: 192 mg(85%).

Methyl4-{[({(1E)-1-aza-2-[3,5-bisphepnylmethoxy)phenyl]vinyl}amino)thioxomethyl]amino}benzoatewas prepared using the procedure for Example 2 from methyl4-[(hydrazinothioxomethyl) amino]benzoate (180 mg; 0.8 mmol) and3,5-dibenzyloxybenzaldehyde (255 mg; 0.8 mmol) as a white solid. Yield:302 mg (72%).

Methyl4-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)benzoatewas prepared using the procedure for Example 2 from methyl4-{[({(1E)-1-aza-2-[3,5-bis(phenyhnethoxy)phenyl]vinyl}amino)thioxomethyl]amino}benzoate (289 mg; 0.55 mmol) and iron(III) chloridehexahydrate (446 mg; 1.65 mmol). Yield: 226 mg (78%). TLC (silica gel):R_(f)=0.69.

The title compound was prepared as in Example 7 using methyl4-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)benzoate(100 mg; 0.19 mmol) and lithium hydroxide (30 mg; 1.25 mmol). Yield: 94mg (97%). mp 297-299° C. Mass (APCI): (MH)⁺: 510 (Calc.); 510 (Obsd.).

Example 50

Ammonium (2E)-3-{4-[5-({3-[(2-phenylphenyl)methylthio]phenyl}amino)(1,3,4-thiadiazol-2-yl)]phenyl}prop-2-enoate

The product from Example 21 (20.5 mg; 0.04 mmol) was dissolved inammonium hydroxide (5 mL) and water (5 mL). The mixture was stirreduntil all solid was in solution. The solvents were removed in vacuo toobtain the title compound as a yellow solid. Yield: 18.5 mg (87%). Mass:(M⁺: 522 (Calc.); 522 (Obsd).

Example 51

{5-[3,5-bis(phenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}){4[3-(trifluoromethyl)phenoxy]phenyl}amine

4-[3-(trifluoromethyl)phenoxy]benzenisothiocyanate was prepared usingProcedure C from 4-[3-(trifluoromethyl)phenoxy]phenylamine (883 mg; 3.5mmol) and thiophosgene (0.53 mL; 7 mmol) as a brown liquid. Yield: 900mg (87%).

Hydrazino({4-[3-(trifluoromethyl)phenoxy]phenyl}amino)methane-1-thionewas prepared using Procedure F from 4-[3-(trifluoromethyl)phenoxy]benzenisothiocyanate (800 mg; 2.7 mmol) and hydrazine hydrate(0.26 mL; 5.4 mmol) as a white solid. Yield: 737 mg (83%).

({(1E)-1-Aza-2-[3,5-bis(phenylmethoxy)phenyl]vinyl}amino)({4-[3-trifluoromethyl)phenoxy]phenyl}amino)methane-1-thione was prepared by the procedure forExample 2 using hydrazino({4-[3-(trifluoromethyl)phenoxy]phenyl}amino)methane-1-thione (327 mg; 1 mmol) and 3,5-dibenzyloxybenzaldehyde (318mg; 1 mmol) as a white solid. Yield: 534 mg (85%).

The title compound was prepared by the procedure for Example 2 from.({(1E)-1-aza-2-[3,5-bisfphenylmethoxy)phenyl]vinyl}amino)(14-[3-(trifluoromethyl)phenoxy]phenylamino)methane-1-thione (377 mg; 0.6 mmol) and iron(I) chloride hexahydrate(486 mg; 1.8 mmol).

Yield: 201 mg (53%). mp 181-183° C. Mass (APCI): (M⁺: 626 (Calc.); 626(Obsd.).

Example 52

2-{4-[3-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)phenoxy]phenyl}aceticacid

Methyl 2-[4-(3-nitrophenoxy)phenyl]acetate was prepared using ProcedureB from methyl-4-hydroxy phenylacetate (3.32 g; 20 mmol) and 3-bromonitrobenzene (4.04 g; 20 mmol), Copper oxide (3.19 g; 40 mmol) andpotassium carbonate (5.54 g; 40 mmol) in pyridine (20 mL).

Yield: 1.4 g (25%).

Methyl 2-[4-(3-isothiocyanatophenoxy)phenyl]acetate was prepared as inProcedure C from the product of Procedure H (1.16 g; 4.5 mmol) andthiophosgene (0.69 mL; 9 mmol) in methylene chloride. Yield: 1.3 g(97%). TLC (silica gel): R_(f)=0.9 (EtOAc/Hexane=1/1).

Methyl 2-(4-{3-[(hydrazinothioxomethyl)amino]phenoxy}phenyl)acetate wasprepared using Procedure F from methyl2-[4-(3-isothiocyanato-phenoxy)phenyl]acetate (1.1 g; 3.6 mmol) andhydrazine hydrate (0.35 mL; 7.2 mmol) in toluene (10 mL). Yield: 1.05 g(88%).

¹H NMR: (300 MHz, DMSO-d₆) 9.20δ (1H, s); 7.68δ (1H, s); 7.29δ (5H, m);6.98δ (2H, d); 6.71δ (1H, d); 3.67δ (2H, s) 3.62δ (3H, s).

Methyl2-[4-(3-{[({(1E)-1-aza-2-[3,5-bis(phenylmethoxy)phenyl]vinyl}amino)thioxomethyl]amino}phenoxy)phenyl]acetate was prepared as in Example 2from methyl 2-(4-{3-[(hydrazinothioxomethyl)amino]phenoxy}phenyl)acetate(331 mg; 1 mmol) and 3,5 dibenzyloxy benzaldehyde (318 mg; 1 mmol) inethanol (5 mL). Yield: 490 mg (77%). Mass (APCI): (M⁺: 632.

Methyl2-{4-[3-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)phenoxy]phenyl}acetate was prepared using the procedure as in Example 2from methyl2-[4-(3-{[({(1E)-1-aza-2-[3,5-bis(phenylmethoxy)phenyl]vinyl}amino)thioxomethyl]amino}phenoxy)phenyl]acetate(379 mg; 0.6 mmol) and Iron chloride (486 mg; 1.8 mmol) in Ethanol.Yield: 146 mg (37%). Mass (APCI): (MH)⁺: 630.

The title compound was prepared as in Example 7 from methyl2-{4-[3-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)phenoxy]phenyl}acetate (100 mg; 0.16 mmol) and lithium hydroxide (24 mg;1 mmol). Yield: 33 mg (34%).

¹H NMR: (300 MHz, DMSO-d₆) 12.30δ (1H, b); 10.66δ (1H, s); 7.38δ (15H,m); 7.28δ (4H, d); 6.82δ (1H, s); 6.25δ (1H, d) 5.18δ (4H, s); 3.57δ(2H, d). Mass: (MH)⁺: 616 (Calc.); 616 (Obsd.).

Example 53

N2-(3-chloro-4-bromophenyl)-5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-amine

3-chloro-4-bromophenyl isothiocyanate and 3-ethoxybenzhydrazide werecombined as described in Example 1 to yield the title compound with anoverall yield of 69%.

¹H NMR (DMSO-d₆) δ 1.36 (t, 3H), 4.12 (q, 2H), 7.08 (m, 1H), 7.43 (m,4H), 7.72 (d, 1H), 8.13 (d, 1H).

¹³C NMR (DMSO-d₆) δ 14.6, 63.3, 112.1, 112.7, 116.6, 117.8, 118.6,119.4, 130.5, 131.2, 133.3, 134.0, 140.8, 158.5, 158.9, 163.4.

Example 54

(3-nitrophenyl)[5-(3-nitrophenyp)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-nitrobenzenecarbohydrazide (500 mg) and 3-nitrobenzenisothiocyanate(500 mg). The title compound had the following physical properties: mp325-330° C. (decomposition).

Example 55

(2-chloro-5-nitrophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from2-chloro-5-nitrobenzenisothiocyanate (100 mg) and3-ethoxybenzenecarbohydrazide (90 mg). The title compound had thefollowing physical properties: mp 128-130° C.

Example 56

[5-(3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)](3-nitrophenyl)amine

The title compound was prepared as described in Example 1 from3-nitrobenzenisothiocyanate (100 mg) and 3-methoxybenzenecarbohydrazide(100 mg). The title compound had the following physical properties: mp206-208° C.

Example 57

[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)](3-nitrophenyl)amine

The title compound was prepared as described in Example 1 from3-nitrobenzenisothiocyanate (100 mg) and 3-ethoxybenzenecarbohydrazide(100 mg). The title compound had the following physical properties: mp155-157° C.

Example 58

[5-(3-methylphenyl)(1,3,4-thiadiazol-2-yl)](3-nitrophenyl)amine

The title compound was prepared as described in Example 1 from3-nitrobenzenisothiocyanate (100 mg) and 3-methylbenzenecarbohydrazide(90 mg). The title compound had the following physical properties: mp219-221° C.

Example 59

[5-3-nitrophenyl)(1,3,4-thiadiazol-2-yl)][3-(trifluoromethyl)-phenyl]amine

The title compound was prepared as described in Example 1 from3-(trifluoromethyl)benzenisothiocyanate (250 mg) and3-nitrobenzenecarbohydrazide (200 mg). The title compound had thefollowing physical properties: mp 266-268° C.

Example 60

(4-ethylphenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-ethylbenzenisothiocyanate (200 mg) and 3-nitrobenzenecarbohydrazide(200 mg). The title compound had the following physical properties: mp208-210° C.

Example 61

(3-methoxyphenyl) [5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-methoxybenzenisothiocyanate (220 mg) and 3-nitrobenzenecarbohydrazide(200 mg). The title compound had the following physical properties: mp207-209° C.

Example 62

(4-nitrophenyl)[5-3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-nitrobenzenisothiocyanate (220 mg) and 3-mitrobenzenecarbohydrazide(200 mg). The title compound had the following physical properties: mp327-329° C.

Example 63

(3-bromophenyl) [5-(3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-bromobenzenisothiocyanate (320 mg) and 3-methoxybenzenecarbohydrazide(250 mg). The title compound had the following physical properties:LC-MS 364.6.

Example 64

(2,5-dibromophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from2,5-dibromobenzenisothiocyanate (300 mg) and3-nitrobenzenecarbohydrazide (190 mg). The title compound had thefollowing physical properties: LC-MS 457.4.

Example 65

(4-bromophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-bromobenzenisothiocyanate (500 mg) and 3-nitrobenzenecarbohydrazide(400 mg). The title compound had the following physical properties:LC-MS 377.4.

Example 66

(4-bromo-3-chlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-bromo-3-chlorobenzenisothiocyanate (500 mg) and3-ethoxybenzenecarbohydrazide (300 mg). The title compound had thefollowing physical properties: mp 204-205° C.; LC-MS 410.6.

Example 67

(3-chloro-4-fluorophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-chloro-4-fluorobenzenisothiocyanate (570 mg) and3-nitrobenzenecarbohydrazide (500 mg). The title compound had thefollowing physical properties: LC-MS 351.3.

Example 68

(3-chloro-4-fluorophenyl)[5-(3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-chloro-4-fluorobenzenisothiocyanate (620 mg) and3-methoxybenzenecarbohydrazide (500 mg). The title compound had thefollowing physical properties: mp 185-187° C.; LC-MS 336.7.

Example 69

(4-bromo-3-chlorophenyl)[5-(3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-bromo-3-chlorobenzenisothiocyanate (650 mg) and3-methoxybenzenecarbohydrazide (400 mg). The title compound had thefollowing physical properties: mp 215-217° C.; LC-MS 398.1.

Example 70

(3-chloro-4-fluorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-chloro-4-fluorobenzenisothiocyanate (260 mg) and3-ethoxybenzenecarbohydrazide (250 mg). The title compound had thefollowing physical properties: mp 170-172° C.; LC-MS 350.5.

Example 71

(4-bromo-3-methylphenyl)[5(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-bromo-3-methylbenzeriisothiocyanate (700 mg) and3-ethoxybenzenecarbohydrazide (500 mg). The title compound had thefollowing physical properties: mp 201-202° C.; LC-MS 392.1.

Example 72

(4-bromo-3-methylphenyl)[5-3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-bromo-3-methylbenzenisothiocyanate (760 mg) and3-methoxybenzenecarbohydrazide (500 mg). The title compound had thefollowing physical properties: mp 190-192° C.; LC-MS 378.4.

Example 73

(4-bromo-3-methylphenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from4-bromo-3-methylbenzenisothiocyanate (690 mg) and3-nitrobenzenecarbohydrazide (500 mg). The title compound had thefollowing physical properties: LC-MS 391.4.

Example 74

(3-bromophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-bromobenzenisothiocyanate (650 mg) and 3-ethoxybenzenecarbohydrazide(500 mg). The title compound had the following physical properties: mp195-197° C.; LC-MS 376.5.

Example 75

Methyl 3-{[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]amino}benzoate

The title compound was prepared as described in Example 1 from methyl3-isothiocyanatobenzoate (500 mg) and 3-nitrobenzenecarbohydrazide (500mg). The title compound had the following physical properties: LC-MS357.5.

Example 76

(2,3-dichlorophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from2,3-dichlorobenzenisothiocyanate (620 mg) and3-nitrobenzenecarbohydrazide (500 mg). The title compound had thefollowing physical properties: mp 240-242° C.; LC-MS 367.3.

Example 77

(3,4-dibromopheny)[5-(3,5-dimethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3,4-dibromobenzenisothiocyanate (280 mg) and3,5-dimethoxybenzenecarbohydrazide (220 mg). The title compound had thefollowing physical properties: mp 240-242° C.; LC-MS 426.1.

Example 78

[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)](3-nitrophenyl)amine.

The title compound was prepared as described in Example 1 from3-nitrobenzenisothiocyanate (4.0 g) and 3-ethoxybenzenecarbohydrazide(4.1 g). The title compound had the following physical properties: mp183-185° C.

Example 79

(5-benzo[3,4-c]1,2,5-oxadiazol-5-yl(1,3,4-thiadiazol-2-yl))(2,3-dichlorophenyl)amine

The title compound was prepared as described in Example 1 from3-methyl-4-bromobenzenisothiocyanate (80 mg) and benzo[c]1,2,5-oxadiazole-5-carbohydrazide (53 mg).

The title compound had the following physical properties: mp 229-231° C.

Example 80

(3-bromophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The title compound was prepared as described in Example 1 from3-bromobenzenisothiocyanate (1.3 g) and 3-nitrobenzenecarbohydrazide(1.0 g). The title compound had the following physical properties: mp273-275° C.; LC-MS 376.88.

Example 81

[5-([2-[(4,5-dichloroimidazolyl)methyl]phenoxy]methyl)(1,3,4-thiadiazol-2-yl)](4-bromo-3-chlorophenyl)amine

Following the procedure described in Example 1, the title compound wasprepared from 4-bromo-3-chlorobenzenisothiocyanate (430 mg) and2-{2-[(4,5-dichloroimidazolylthio)methyl]phenoxy}acetohydrazide (500mg). The title compound had the following physical properties: mp183-185° C.

Example 82

[(4-methylphenyl)sulfonyl](4-{[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amino}phenyl)amine

Following the procedure described in Example 10 (with sulfonyl chloridein place of acyl chloride), the title compound was prepared from(4-{[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amino}phenyl)amine (100mg) and 4-toluenesulfonyl chloride (96 mg). The title compound had thefollowing physical properties: mp 255-257° C.

Example 83

(4-{[5(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]aminophenyl)-(phenylsuffonyl)amine

As described in Example 10 (with sulfonyl chloride in place of acylchloride), the title compound was prepared from(4-{[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amino}phenyl) amine (100mg) and benzenesulfonyl chloride (100 mg). The title compound had thefollowing physical properties: mp 216-218° C.

Example 84

[(4-{[5(3-Nitrophenyl)-1,3,4-thiadiazol-2-yl]amine}phenyl)sulfonyl]piperidine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and4-(piperidylsulfonyl) benzenisothiocyanate (565 mg; 2.0 mmol) to yield(3-nitrophenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(910 mg, 98%) in the first step. In the second step,(3-nitrophenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(800 mg; 1.7 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (751 mg; 98%) with the following physical properties: mp266-267° C.; Mass (M+1)⁺446 (Calc.); 446 (Obsd.). (A&A)

Example 85

(4-Bromo-3-chlorophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and4-bromo-3-chlorobenzenisothiocyanate (497 mg; 2.0 mmol) to yieldN-({[(4-bromo-3-chlorophenyl)amino]thioxo-methyl}amino)(3-nitrophenyl)carboxamide(810 mg; 94%) in the first step. In the second step,N-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(750 mg; 1.7 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (698 mg; 97%) with the following physical properties: mp330-331° C.; Mass (M+1)⁺413 (Calc.); 413 (Obsd.). (A&A)

Example 86

[5-(3-Nitrophenyl)(1,3,4-thiadiazol-2-yl)(2,3,4,5-tetrachlorophenyl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and2,3,4,5-tetrachlorobenzenisothiocyanate (546 mg; 2.0 mmol) to yield(3-nitrophenyl)-N-({[(2,3,4,5-tetrachlorophenyl)amino]thioxomethyl}amino)carboxamide (690 mg; 76%) in the first step. In the second step,(3-nitrophenyl)-N-({[(2,3,4,5-tetrachlorophenyl)amino]thioxomethyl}amino)carboxamide (550 mg; 1.2 mmol) and sulfuric acid (2.0 mL) were used toyield the title compound (516 mg; 98%) with the following physicalproperties: mp 250-251° C.; Mass (M+1)⁺437 (Calc.); 437 (Obsd.). (A&A)

Example 87

(3-Chloro-4-methylphenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and3-chloro-4-methylbenzenisothiocyanate (367 mg; 2.0 mmol) to yieldN-({[(3-chloro-4-methylphenyl)amino]thioxomethyl}amino)-(3-nitrophenyl)carboxamide(700 mg; 96%) in the first step. In the second step,N-({[(3-chloro-4-methylphenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(550 mg; 1.5 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (486 mg; 93%) with the following physical properties: mp289-290° C.; Mass (M)⁺347 (Calc.); 347 (Obsd.); Elemental analysis C,51.95; H, 3.20; N, 16.16, S 9.25 (Calc.); C52.12, H 3.16, N 16.16, S9.42 (Obsd.). (NuMega)

Example 88

(4-Methylthiophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and4-methylthiobenzenisothiocyanate (362 mg; 2.0 mmol) to yieldN-({[(4-methylthiophenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(710 mg; 98%) in the first step. In the second step,N-({[(4-methylthiophenyl)aminolthioxomethyl}amino)(3-nitrophenyl)carboxamide(600 mg; 1.7 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (528 mg; 93%) with the following physical properties: mp247-248° C.; Mass (M+1)⁺345 (Calc.); 345 (Obsd.). (NuMega)

Example 89

[4-Methylethyl)phenyl][5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and4-(methylethyl)benzenisothiocyanate (354 mg; 2.0 mmol) to yieldN-({[(4-(methylethyl)phenyl)amino]thioxomethylgamino)-(3-nitrophenyl)carboxamide(680 mg; 94%) in the first step. In the second step,N-({[(4-(methylethyl)phenyl)amino]thioxomethyl}amino)-(3-nitrophenyl)carboxamide(600 mg; 1.7 mmol) and sulfuiric acid (2.0 mL) were used to yield thetitle compound (516 mg; 90%) with the following physical properties: mp243-244° C.; Mass (M+1)⁺341 (Calc.); 341 (Obsd.); (M+23)⁺363 (Calc.);363 (Obsd.). (NuMega)

Example 90

(4-Butylphenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and4-butylbenzenisothiocyanate (383 mg; 2.0 mmol) to yieldN-({[(4-butylphenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(680 mg; 92%) in the first step. In the second step,N-({[(4-butylphenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(500 mg; 1.3 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (428 mg; 90%) with the following physical properties: mp198-199° C.; Mass (M+1)⁺355 (Calc.); 355 (Obsd.). (A&A)

Example 91

(4-Decylphenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (154 mg; 0.8 mmol) and4-decylbenzenisothiocyanate (237 mg; 0.8 mmol) to yieldN-({[(4-decylphenyl)amino]thioxomethyl}amino)-(3-nitrophenyl)carboxamide(340 mg; 87%) in the first step. In the second step,N-({[(4-decylphenyl)amino]thioxomethyl}amino)-(3-nitrophenyl)carboxamide(300 mg; 0.7 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (264 mg; 92%) with the following physical properties: mp169-171° C.; Mass (M+1)⁺440 (Calc.); 440 (Obsd.). (A&A)

Example 92

[5-(3-Nitrophenyl)(1,3,4-thiadiazol-2-yl)[4-(4-nitrophenoxy)phenyl]amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and4-(4-nitrophenoxy)benzenisothiocyanate (545 mg; 2.0 mmol) to yield(3-nitrophenyl)-N-[({[4-(4-nitrophenoxy)phenyl]amino}thioxomethyl)amino]carboxamide(890 mg; 98%) in the first step. In the second step,(3-nitrophenyl)-N-[({[4-4-nitrophenoxy)phenyl]amino}thioxomethyl)amino]carboxamide(500 mg; 1.1 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (480 mg; 100%) with the following physical properties: mp285-286° C.; Mass (M+1)⁺436 (Calc.); 436 (Obsd.). (A&A)

Example 93

[(4-{[5-(3-Methoxyphenyl}1,3,4-thiadiazol-2-yl]aminelphenyl)sulfonyl]piperidine

The reactions described in Example 1 were repeated using3-methoxybenzenecarbohydrazide (332 mg; 2.0 mmol) and4-(piperidylsulfonyl) benzenisothiocyanate (565 mg; 2.0 mmol) to yield(3-methoxyphenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(775 mg; 86%) in the first step. In the second step,(3-methoxyphenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(500 mg; 1.1 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (751 mg; 980%) with the following physical properties: mp205-206° C.; Mass (+1)+432 (Calc.); 432 (Obsd.). (A&A)

Example 94

[(4-{[5-(3-Methylphenyl)-1,3,4-thiadiazol-2-yl]amine}phenyl)sulfonyl]piperidine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (300 mg; 2.0 mmol) and4-(piperidylsulfonyl) benzenisothiocyanate (565 mg; 2.0 mmol) to yield(3-methylphenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(757 mg; 88%) in the first step. In the second step,(3-methylphenyl)-N-[({([4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(500 mg; 1.2 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (751 mg; 98%) with the following physical properties: mp213-214° C.; Mass (M+1)⁺415 (Calc.); 415 (Obsd.). (A&A)

Example 95

(5-Chloro-2,4-dimethoxyphenyl)[5-3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 1 were repeated using3-nitrobenzenecarbohydrazide (362 mg; 2.0 mmol) and5-chloro-2,4-dimethoxybenzenisothiocyanate (459 mg; 2.0 mmol) to yieldN-({[(5-chloro-2,4-dimethoxyphenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(796 mg; 97%) in the first step. In the second step,N-({[(5-chloro-2,4-dimethoxyphenyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(550 mg; 1.3 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (470 mg; 89%) with the following physical properties: mp218-219° C.; Mass (M)⁺393 (Calc.); 393 (Obsd.). (A&A)

Example 96

(3-Chloro-4-methylphenyl){5-[3-(phenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

As described in Procedure D,[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (3.38 g, 78%)was prepared from 3-chloro-4-methylbenzenisothiocyanate (3.67 g; 20mmol) and hydrazine monohydrate (1.50 g; 30 mmol).

The reactions described in Example 2 were repeated using[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (216 mg; 1.0mmol) and 3-(phenylmethoxy)benzaldehyde (212 mg; 1.0 mmol) to yield({1-aza-2-[3-(phenylmethoxy)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(320 mg; 78%) in the first step. In the second step,({1-aza-2-[3-(phenylmethoxy)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(205 mg; 0.5 mmol) and iron (III) chloride hexahydrate (405 mg; 1.5mmol) were used to yield the title compound (80 mg, 39%) with thefollowing physical properties: mp 211-212° C.; Mass (M)⁺408 (Calc.); 408(Obsd.). (A&A)

Example 97

(3-Chloro-4-methylphenyl)[5-(4-morpholin-4-yl-3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 2 were repeated using[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (216 mg; 1.0mmol) and 4-morpholin-4-yl-3-nitrobenzaldehyde (236 mg; 1.0 mmol) toyield{[1-aza-2-(4-morpholin-4-yl-3-nitrophenyl)vinyl]amino}[(3-chloro-4-methylphenyl)amino]methane-1-thione(330 mg, 77%) in the first step. In the second step,{[1-aza-2-(4-morpholin-4-yl-3-nitrophenyl)vinyl]amino}[(3-chloro-4-methylphenyl)amino]methane-1-thione(217 mg; 0.5 mmol) and iron (III) chloride hexahydrate (405 mg; 1.5mmol) were used to yield the title compound (83 mg, 38%) with thefollowing physical properties: mp 268-269° C.; Mass (M)⁺432 (Calc.); 432(Obsd.). (A&A)

Example 98

2-(3-{5[(3-Chloro-4-methylphenyl)amino]-1,3,4-thiadiazol-2-ylphenoxy)ethan-1-ol

The reactions described in Example 2 were repeated using[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (216 mg; 1.0mmol) and 3-(2-hydroxyethoxy)benzaldehyde (166 mg; 1.0 mmol) to yield2-{3-[2-aza-2-({[(3-chloro-4-methylphenyl)amino]thioxomethyl}amino)vinyl]phenoxy}ethan-1-ol(145 mg, 40%) in the first step. In the second step,2-{3-[2-aza-2-({[(3-chloro-4-methylphenyl)amino]thioxomethyl}amino)vinyl]phenoxy}ethan-1-ol(104 mg; 0.3 mmol) and iron (I) chloride hexahydrate (243 mg; 0.9 mmol)were used to yield the title compound (42 mg, 23%) with the followingphysical properties: mp 193-194° C.; Mass (M+1)⁺363 (Calc.); 363(Obsd.). (A&A)

Example 99

(3-Chloro-4-methylphenyl){5-[4-(trifluoromethylthio)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (216 mg; 1.0mmol) and 4-(trifluoromethylthio)benzaldehyde (206 mg; 11.0 mmol) toyield({1-aza-2-[4-(trifluoromethylthio)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(268 mg, 66%) in the first step. In the second step,({1-aza-2-[4-(trifluoromethylthio)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(202 mg; 0.5 mmol) and iron (1H) chloride hexahydrate (405 mg; 1.5 mmol)were used to yield the title compound (89 mg, 44%) with the followingphysical properties: mp 215-216° C.; Mass (M)⁺402 (Calc.); 402 (Obsd.).(A&A)

Example 100

[(4-{[5-(4-Bromo-3-chlorophenyl)-1,3,4-thiadiazol-2-yl]amine}phenyl)sulfonyl]piperidine

The reactions described in Example 1 were repeated using1-bromo-2-chlorobenzene-4-carbohydrazide (250 mg; 1.0 mmol) and4-(piperidylsulfonyl) benzenisothiocyanate (282 mg; 1.0 mmol) to yield(4-bromo-3-chlorophenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(510 mg, 96%) in the first step. In the second step,(4-bromo-3-chlorophenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(800 mg; 1.7 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (394 mg; 90%) with the following physical properties: mp262-263° C.; Mass (M+1)+515 (Calc.); 515 (Obsd.). (A&A)

Example 101

[(4-{[5-3-Bromo-4-chlorophenyl)-1,3,4-thiadiazol-2-yl]amine}phenyl)sulfonyl]piperidine

The reactions described in Example 1 were repeated using2-bromo-1-chlorobenzene-4-carbohydrazide (250 mg; 1.0 mmol) and4-(piperidylsulfonyl) benzenisothiocyanate (282 mg; 1.0 mmol) to yield(3-bromo-4-chlorophenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(510 mg; 96%) in the first step. In the second step,(3-bromo-4-chlorophenyl)-N-[({[4-(piperidylsulfonyl)phenyl]amino}thioxomethyl)amino]carboxamide(450 mg; 0.8 mmol) and sulfuric acid (2.0 mL) were used to yield thetitle compound (412 mg; 95%) with the following physical properties: mp246-247° C.; Mass (M+1)⁺515 (Calc.); 515 (Obsd.). (A&A)

Example 102

(3-Chloro-4-methylphenyl){5-[3-trifluoromethoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (216 mg; 1.0mmol) and 3-(trfluoromethoxy)benzaldehyde (190 mg; 1.0 mmol) to yield({1-aza-2-[3-(trifluoromethoxy)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(262 mg; 68%) in the first step. In the second step,({1-aza-2-[3-(trifluoromethoxy)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(194 mg; 0.5 mmol) and iron (1H) chloride hexahydrate (405 mg; 1.5 mmol)were used to yield the title compound (46 mg; 32%) with the followingphysical properties: mp 180-181° C.; Mass (M)⁺386 (Calc.); 386 (Obsd.).(A&A)

Example 103

(5-{3-[4-(ter-Butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(3-chloro-4-methylphenyl)amine

The reactions described in Example 2 were repeated using[(3-chloro-4-methylphenyl)amino]hydrazinomethane-1-thione (216 mg; 1.0mmol) and 3-[4-(tert-butyl)phenoxy]benzaldehyde (254 mg; 1.0 mmol) toyield[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino][(3-chloro-4-methylphenyl)amino]methane-1-thione(333 mg; 74%) in the first step. In the second step,[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino][(3-chloro-4-methylphenyl)amino]methane-1-thione(226 mg; 0.5 mmol) and iron (E) chloride hexahydrate (405 mg; 1.5 mmol)were used to yield the title compound (50 mg, 22%) with the followingphysical properties: mp 187-189° C.; Mass (M)⁺450 (Calc.); 450 (Obsd.).(A&A)

Example 104

(3,4-Dichlorophenyl){5-[4-methoxy-3-(phenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using the productfrom Procedure D (236 mg; 1.0 mmol) and4-methoxy-3-(phenylmethoxy)benzaldehyde (242 mg; 1.0 mmol) to yield({1-aza-2-[4-methoxy-3-(phenylmethoxy)phenyl]vinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thione(439 mg; 95%) in the first step. In the second step,({1-aza-2-[4-methoxy-3-(phenylmethoxy)phenyl]vinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thione(322 mg; 0.7 mmol) and iron (m) chloride hexahydrate (568 mg; 2.1 mmol)were used to yield the title compound (127 mg; 40%) with the followingphysical properties: mp 223-224° C.; Mass (M+1)⁺459 (Calc.); 459(Obsd.). (A&A)

Example 105

(3,4-Dichlorophenyl){5[4-(difluoromethoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using the productfrom Procedure D (236 mg; 1.0 mmol) and 4-(difluoromethoxy)benzaldehyde(172 mg; 1.0 mmol) to yield({1-aza-2-[4-(difluoromethoxy)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(332 mg, 85%) in the first step. In the second step,({1-aza-2-[4-(difluoromethoxy)phenyl]vinyl}amino)[(3-chloro-4-methylphenyl)amino]methane-1-thione(234 mg; 0.6 mmol) and iron (m) chloride hexahydrate (486 mg; 1.8 mmol)were used to yield the title compound (134 mg; 58%) with the followingphysical properties: mp 265-266° C.; Mass (M)⁺388 (Calc.); 388 (Obsd.).(A&A)

Example 106

(3,4-Dichlorophenyl)[5-(4-butoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 2 were repeated using the productfrom Procedure D (236 mg; 1.0 mmol) and 4-butoxybenzaldehyde (178 mg;1.0 mmol) to yield{[1-aza-2-(3-butoxyphenyl)vinyl]amino}[(3,4-ichlorophenyl)amino]methane-1-thione(303 mg; 76%) in the first step. In the second step,{[1-aza-2-(3-butoxyphenyl)vinyl]amino}[(3,4-dichlorophenyl)amino]methane-1-thione(238 mg; 0.6 mmol) and iron ([) chloride hexahydrate (486 mg; 1.8 mmol)were used to yield the title compound (112 mg; 47%) with the followingphysical properties: mp 233-235° C.; Mass (M)+394 (Calc.); 394 (Obsd.).

Example 107

2-(4-{5-[(3,4-Dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenoxy)-1-(4-methylpiperidyl)ethan-1-one

The reactions described in Example 2 were repeated using the productfrom Procedure D (2.36 g; 10.0 mmol) and 2-(3-formylphenoxy)acetic acid(1.80 g; 10.0 mmol) to yield2-{3-[2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)vinyl]phenoxy}aceticacid (4.05 g; 95%) in the first step. In the second step,2-{3-[2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)vinyl]phenoxy}aceticacid (3.38 g; 7.9 mmol) and iron (III) chloride hexahydrate (6.43 g;25.0 mmol) were used to yield ethyl2-(3-{5-[(3,4-dichlorophenyl)amino]-1,3;4-thiadiazol-2-yl}phenoxy)acetate(2.16 g; 64%).

A solution of 4-methylpiperidine (1.98 g; 20 mmol) and ethyl2-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)acetate(420 mg; 1 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aftercooling, a white solid was provided (280 mg, 59%): mp 219-220° C.; Mass(M)⁺477 (Calc.); 477 (Obsd.).

Example 108

(5-{3-[4-tert-Butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))indan-2-ylamine

As described in Procedure D, hydrazino(indan-2-ylamino)methane-1-thione(2.07 g; 100%) was prepared from indan-2-isothiocyanate (1.75 g; 10.0mmol) and hydrazine monohydrate (750 mg; 15.0 mmol).

The reactions described in Example 2 were repeated using ofhydrazino(indan-2-ylamino)methane-1-thione (415 mg; 2.0 mmol) and3-[4-(tert-butyl)phenoxy]benzaldehyde (509 mg; 2.0 mmol) to yield[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino](indan-2-ylamino)methane-1-thione(491 mg; 55%) in the first step. In the second step,[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino](indan-2-ylamino)methane-1-thione(444 mg; 1.0 mmol) and iron (III) chloride hexahydrate (811 mg; 3.0mmol) were used to yield the title compound (109 mg; 25%) with thefollowing physical properties: mp 132-133° C.; Mass (M)⁺442 (Calc.); 442(Obsd.).

Example 109

(5-{3-[4-(tert-Butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(3,3,5-trimethylcyclohexyl)amine

As described in Procedure D,hydrazino[(3,3,5-trimethylcyclohexyl)amino]methane-1-thione (1.16 g;98%) was prepared from 3,3,5-trimethylcyclohexanisothiocyanate (1.01 g;5.5 mmol) and hydrazine monohydrate (400 mg; 8.0 mmol).

The reactions described in Example 2 were repeated usinghydrazino[(3,3,5-trimethylcyclohexyl)amino]methane-1-thione (431 mg; 2.0mmol) and 3-[4-(tert-butyl)phenoxy]benzaldehyde (509 mg; 2.0 mmol) toyield[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino][(3,3,5-trimethylcyclohexyl)amino]methane-1-thione(484 mg; 54%) in the first step. In the second step,[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino][(3,3,5-trimethylcyclohexyl)amino]methane-1-thione(452 mg; 11.0 mmol) and iron (III) chloride hexahydrate (811 mg; 3.0mmol) were used to yield the title compound (240 mg, 53%) with thefollowing physical properties: mp 166-167° C.; Mass (M)⁺450 (Calc.); 450(Obsd.).

Example 110

(5-{3-[4-(tert-Butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(methylhexyl)amine

As described in Procedure D,hydrazino[(methylhexyl)amino]methane-1-thione (1.81 g; 96%) was preparedfrom heptan-2-isothiocyanate (1.57 g; 10.0 mmol) and of hydrazinemonohydrate (750 mg; 15.0 mmol).

The reactions described in Example 2 were repeated usinghydrazino[(methylhexyl)amino]methane-1-thione (379 mg; 2.0 mmol) and3-[4-(tert-butyl)phenoxy]benzaldehyde (509 mg; 2.0 mmol) to yield[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino][(methylhexyl)amino]methane-1-thione(320 mg, 78%) in the first step. In the second step,[(1-aza-2-{3-[4-(tert-butyl)phenoxy]phenyl}vinyl)amino][(methylhexyl)amino]methane-1-thione(425 mg; 1.0 mmol) and iron (III) chloride hexahydrate (811 mg; 3.0mmol) were used to yield the title compound (211 mg; 50%) with thefollowing physical properties: mp 115-116° C.; Mass (M)⁺424 (Calc.); 424(Obsd.).

Example 111

(5-{3-[3-(Trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(3,3,5-trimethylcyclohexyl)amine

The reactions described in Example 2 were repeated usinghydrazino[(3,3,5-trimethylcyclohexyl)amino]methane-1-thione (431 mg; 2.0mmol) and 3-[3-(trifluoromethyl)phenoxy]benzaldehyde (532 mg; 2.0 mmol)to yield[(1-aza-2-{3-[3-(trifluoromethyl)phenoxy]phenyl}vinyl)amino][(3,3,5-trimethylcyclohexyl)amino]methane-1-thione(420 mg; 45%) in the first step. In the second step,[(1-aza-2-{3-[3-(trifluor-omethyl)phenoxy]phenyl}vinyl)amino][(3,3,5-triethylcyclohexyl)amino]methane-1-thione(400 mg; 0.9 mmol) and iron (III) chloride hexahydrate (700 mg; 2.6mmol) were used to yield the title compound (121 mg; 30%) with thefollowing physical properties: mp 101-102° C.; Mass (M)⁺462 (Calc.); 462(Obsd.).

Example 112

2-[4-(henylmethoxy)phenyl]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))acetamide

The reactions described in Example 10 were repeated using the productfrom Example 23 (202 mg; 0.6 mmol), 2-[4-(phenylmethoxy)phenyl]acetylchloride (313 mg; 1.2 mmol) and dimethyl-4-pyridylamine (244 mg; 2.0mmol) to yield the title compound (107 mg; 32%) with the followingphysical properties: mp 194-195° C.; Mass (M)⁺562 (Calc.); 562 (Obsd.).

Example 113

Naphthyl-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

The reactions described in Example 10 were repeated using the productfrom Example 23 (202 mg; 0.6 mmol), naphthalene-2-carbonyl chloride (229mg; 1.2 mmol) and dimethyl-4-pyridylamine (244 mg; 2.0 mmol) to yieldthe title compound (241 mg; 82%) with the following physical properties:mp 236-238° C.; Mass (M+1)+492 (Calc.); 492 (Obsd.).

Example 114

2-[(3-{5-[(3,4-Dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methoxy]aceticacid.

The reactions described in Example 7 were repeated using ethyl2-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methoxy]acetate(210 mg; 0.4 mmol), lithium hydroxide (72 mg; 3 mmol), MeOH/H₂O (3:1) (5mL) and THF (3 mL) to yield the title compound (55 mg; 28%) with thefollowing physical properties: mp 89-91° C.; Mass (M)⁺554 (Calc.); 554(Obsd.).

Example 115

2-[4-(tert-Butyl)phenoxy]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))acetamide

The reactions described in Example 10 were repeated using the productfrom Example 23 (202 mg; 0.6 mmol), 2-[4-(tert-butyl)phenoxy]acetylchloride (181 mg; 0.8 mmol) and dimethyl-4-pyridylamine (244 mg; 2.0mmol) to yield the title compound (110 mg; 35%) with the followingphysical properties: mp 179-180° C.; Mass (M)+528 (Calc.); 528 (Obsd.).

Example 116

[2-(4-Methoxyphenoxy)-5-nitrophenyl]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

The reactions described in Example 10 were repeated using the productfrom Example. 23 (202 mg; 0.6 mmol), 2-(4-methoxyphenoxy)-5-nitrobenzoylchloride (246 mg; 0.8 mmol) and dimethyl-4-pyridylamine (244 mg; 2.0mmol) to yield the title compound (15 mg; 4%) with the followingphysical properties: mp 130-132° C.; Mass)⁺609 (Calc.); 609 (Obsd.).

Example 117

[5-(3,5-Dichlorophenloxy)(2-furyl)]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

The reactions described in Example 10 were repeated using the productfrom Example 23 (202 mg; 0.6 mmol),5-(3,5-dichlorophenoxy)furan-2-arbonyl chloride (233 mg; 0.8 mmol) anddimethyl-4-pyridylamine (244 mg; 2.0 mmol) to yield the title compound(30 mg; 8%) with the following physical properties: mp 205-207° C.; Mass(M)+592 (Calc.); 592 (Obsd.).

Example 118

(3-Nitrophenyl)-N-(5-3-[3-(trilluoromethyl)phenoxy]phenyl)(1,3,4-thiadiazol-2-yl))carboxamide

The reactions described in Example 10 were repeated using the productfrom Example 23 (202 mg; 0.6 mmol), 3-nitrobenzoyl chloride (148 mg; 0.8mmol) and dimethyl-4-pyridylamine (244 mg; 2.0 mmol) to yield the titlecompound (72 mg; 25%) with the following physical properties: mp200-202° C.; Mass (M+1)+487 (Calc.); 487 (Obsd.).

Example 119-120

3-{2-[aza(4-bromo-3-chlorophenyl)methylene]-3-benzyl(1,3,4-thiadiazoln-5yl))-1-phenoxybenzene

and

(4-bromo-3-chlorophenyl)benzyl[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The reaction described in Example 8 was repeated using(4-bromo-3-chlorophenyl)[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(126 mg; 0.27 mmol), potassium tert-butoxide (0.27 mL; 0.27 mmol) andbenzyl bromide (0.039 mL; 0.33 mmol) to yield3-{2-[aza(4-bromo-3-chlorophenyl)methylene]-3-benzyl(1,3,4-thiadiazolin-5-yl)}-1-phenoxybenzene(21 mg; 19%) with the following physical properties: Rf: 0.56(hexanes/ethyl acetate, 2/1); MS (M)⁺: 547, 549, 551.

¹H NMR (300 MHz, di-CDCl₃): δ 7.53 (1H, d), 7.45 (2H, d), 7.38-7.30 (8H,m), 7.18-7.11 (2H, m), 7.02-6.70 (3H, m), 6.85 (1H, dd), 5.31 (2H, s),and

(4-bromo-3-chlorophenyl)benzyl[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(44 mg; 30%) with the following physical properties: R_(f): 0.45(hexanes/ethyl acetate, 2/1); MS (M)⁺: 547, 549, 551;

¹H NMR (300 MHz, di-CDCl₃): δ 7.59 (1H, d), 7.46-7.44 (3H, m), 7.37-7.28(8H, m), 7.15-7.01 (5H, m), 5.20 (2H, s).

Example 121

2-{5-[(4-bromo-3-chlorophenyl)amino]-1,3,4-thiadiazol-2-yl}-3-hydroquinazolin-4-one

The reactions described in Example 1 were repeated using4-oxo-3-hydroquinazoline-2-carbohydrazide (100 mg; 0.49 mmol) and4-bromo-3-chlorobenzenisothiocyanate (122 mg; 0.49 mmol) to yieldN-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)(4-oxo(3-hydroquinazolin-2-yl))carboxamide in thefirst step. In the second step, all the crude product and sulfuric acid(0.4 mL) were used to yield the title compound (85 mg; 40%) with thefollowing physical properties: mp 348-349° C.; MS (M)⁺: 433, 435, 437.

Example 122

(5-benzo[3,4-c]1,2,5-oxadiazol-5-yl(1,3,4-thiadiazol-2-yl))(4-bromo-3-chlorophenyl)amine

The reactions described in Example 1 were repeated usingbenzo[c]1,2,5-oxadiazole-5-carbohydrazide (150 mg; 0.84 mmol) and4-bromo-3-chlorobenzenisothiocyanate (209 mg; 0.49 mmol) to yieldbenzo[3,4-c]1,2,5-oxadiazol-5-yl-N-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)carboxamidein the first step. In the second step, all the crude product andsulfuric acid (0.5 mL) were used to yield the title compound (272 mg;79%) with the following physical properties: mp 326-327° C.; Anal. Calcdfor C₁₄H₇BrClN₅OS: C, 41.15; H, 1.73; N, 17.14; S, 7.85. Found: C,41.28; H, 1.62; N, 16.93; S, 8.01.

Example 123

ethyl 4-{[5-(4-phenoxyphenyl)-1,3,4-thiadiazol-2-yl]amino}benzoate

The reactions described in Example 1 were repeated using1-phenoxybenzene-4-carbohydrazide (500 mg; 2.2 mmol) and ethyl4-isothiocyanatobenzoate (454 mg; 2.2 mmol) to yield ethyl4-[({[(4-phenoxyphenyl)carbonylamino]amino}thioxomethyl)amino]benzoatein the first step. In the second step, all the crude product andsulfuric acid (0.5 mL) were used to yield the title compound (589 mg;64%) with the following physical properties: mp 206-207° C.; MS (M+H)⁺:418.

Example 124

(3,4-dichlorophenyl)[5-(3-{[4-(tert-butl)phenyl]methoxy}phenyl)(1,3,4-thiadiazol-2-yl)]{[4-(tert-butyl)phenyl]methyl}amine

The reaction described in Example 8 was repeated using3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenol (200 mg;0.59 mmol), potassium tert-butoxide (1.18 mL; 1.18 mmol) and1-(tert-butyl)-4-(bromomethyl)benzene (0.1 mL; 0.59 mmol) to yield thetitle compound (168 mg; 45%) with the following physical properties:

¹H NMR (300 MHz, di-CDCl₃): δ 7.50-7.18 (14H, m), 7.04-7.00 (1H, m),5.19 (2H, s), 5.06 (2H, s), 1.33 (9H, s), 1.29 (9H, s).

Example 125

5-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}-3-[3-trifluoromethyl)phenoxy]phenol

The reactions described in Procedure B were followed using methyl3,5-dihydroxybenzoate (5.00 g; 29.7 mmol),1-bromo-3-(trifluoromethyl)benzene (6.2 mL; 44.5 mmol), potassiumcarbonate (8.22 g; 59.5 mmol), copper(II) oxide (4.73 g; 59.5 mmol) andpyridine (30 mL) to yield methyl5-hydroxy-3-[3-(trifluoromethyl)phenoxy]benzoate (1.22 g; 13%) as whitesolid.

¹H NMR (300 MHz, di-CDCl₃): δ 7.49-7.37 (3H, m), 7.26-7.17 (3H, m), 6.74(1H, s), 6.10 (1H, br s), 3.90 (3H, s).

A solution of methyl 5-hydroxy-3-[3-(trifluoromethyl)phenoxy]benzoate(1.22 g; 3.9 mmol) and hydrazine monohydrate (0.38 mL; 7.8 mmol) in dryethanol (4.5 mL) under nitrogen was refluxed for 30 hours. After coolingto RT, the solvent was removed by rotovapor. The residue was wash bywater then hexanes, dried by vacuum to yield5-hydroxy-3-[3-(trifluoromethyl)phenoxy]benzenecarbohydrazide (980 mg;80%) as a light yellow solid.

The reactions described in Example 1 were repeated using5-hydroxy-3-[3-(trifluoromethyl)phenoxy]benzenecarbohydrazide (500 mg;1.6 mmol) and 3,4-dichlorobenzenisothiocyanate (327 mg; 1.6 mmol) toyield N-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino){3-[3-(trifluoromethyl)phenoxy]phenyl}carboxamide in the first step. Inthe second step, all the crude product and sulfuric acid (0.8 mL) wereused to yield the title compound (712 mg; 89%) with the followingphysical properties: mp 193-194° C.; MS (M)⁺: 497, 499.

Example 126

(3,4-dichlorophenyl){5-[3-(3-nitrophenoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Procedure B were followed using(3-hydroxyphenyl) formaldehyde (5.00 g; 40.9 mmol),1-bromo-3-nitrobenzene (9.925 g; 49.1 mmol), potassium carbonate (11.318g; 81.9 mmol), copper(II) oxide (6.513 g; 81.9 mmol) and pyridine (50mL) to yield [3-(3-nitrophenoxy)phenyl]formaldehyde (2.49 g; 25%) aslight yellow solid.

¹H NMR (300 MHz, d₁-CDCl₃): δ 10.01 (1H, s), 8.01 (1H, dd), 7.83 (1H,t), 7.73 (1H, d), 7.63-7.52 (3H, m), 7.39-7.33 (2H, m).

The reactions described in Example 2 were repeated using[3-(3-nitrophenoxy)phenyl]formaldehyde (2.240 g; 9.2 mmol) and theproduct from Procedure D (2.177 g; 9.2 mmol) to yield({(1E)-1-aza-2-[3-(3-nitrophenoxy)phenyl]vinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thionein the first step. In the second step, all the crude product andiron(II) chloride hexahydrate (7.47 g; 27.6 mmol) were used to yield thetitle compound (3.71 g; 88%) with the following physical properties: mp210.5-211.5° C.; MS (M)⁺: 458, 460.

Example 127

2-[3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]aceticacid

The reactions described in Procedure B were followed using(3-bromophenyl)formaldehyde (2.95 g; 15.96 mmol), methyl2-(3-hydroxyphenyl)acetate (2.56 g; 15.96 mmol), potassium carbonate(4.41 g; 31.93 mmol), copper(II) oxide (2.54 g; 31.93 mmol) and pyridine(20 mL) to yield methyl 2-[3-(3-carbonylphenoxy)phenyl]acetate (532 mg;12%) as a colorless oil.

¹H NMR (300 MHz, d₁-CDCl₃): δ 9.96 (1H, s), 7.61 (1H, d), 7.53-7.47 (2H,m), 7.35-7.26 (2H, m), 7.08 (1H, d), 6.99 (1H, s), 6.94 (1H, d), 3.70(3H, s), 3.62 (2H, s).

The reactions described in Example 2 were repeated using methyl2-[3-(3-carbonylphenoxy)phenyl]acetate (532 mg; 1.97 mmol) and theproduct from Procedure D (465 mg; 1.97 mmol) to yield methyl2-(3-{3-[(1E)-2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)vinyl]phenoxy}phenyl)acetatein the first step. In the second step, all the crude product andiron(III) chloride hexahydrate (1.597 g; 5.9 mmol) were used to yieldmethyl2-[3-(3-{5-[(3,4-dichlorophenyl)amino-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]acetate(491 mg; 51%).

The reaction described in Example 7 was repeated using methyl2-[3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]acetate(140 mg; 0.29 mmol) and lithium hydroxide (20 mL; 0.25______) to yieldthe title compound (123 mg; 91%) with the following physical properties:mp 183-184° C.; MS (M)⁺: 471, 473.

Example 128

4-(3-{-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenol

The reactions described in Procedure B were followed using4-hydroxyphenyl benzoate (3.00 g; 14.0 mmol),(3-bromophenyl)formaldehyde (3.3 mL; 28.0 mmol), potassium carbonate(3.87 g; 28.0 mmol), copper(II) oxide (2.23 g; 28.0 mmol) and pyridine(15 mL) to yield 4-(3-carbonylphenoxy)phenyl benzoate (305 mg; 9%) and[3-(4-hydroxyphenoxy)phenyl]formaldehyde (417 mg; 14%).

The reactions described in Example 2 were repeated using[3-(4-hydroxyphenoxy) phenyl]formaldehyde (306 mg; 1.4 mmol) and theproduct from Procedure D (337 mg; 1.4 mmol) to yield4-{3-[(1E)-2-aza-2-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)vinyl]phenoxy}phenolin the first step. In the second step, all the crude product and iron(M) chloride hexahydrate (1.159 g; 4.3 mmol) were used to yield thetitle compound (332 mg; 55%) with the following physical properties: mp224-225.5° C.; MS (M)⁺: 429, 431.

Example 129

(3,4-dichlorophenyl)[5-(3-{[3-(trifluoromethoxy)phenyl]methoxy}phenyl)(1,3,4-thiadiazol-2-yl)]amine

To a solution of3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenol (150 mg;0.44 mmol) in dry DMF (5 mL) was added a solution of potassiumtert-butoxide (0.44 mL, 1M, 0.44 mmol) in THF at RT under an argonatmosphere. After 5 minutes, [3-(bromomethyl)phenoxy]trifluoromethane(0.086 mL; 0.53 mmol) was injected, and the solution was stirredovernight. The DMF was evaporated (rotovap) under vacuum. The cruderesidue was purified by flash chromatography (ethyl acetate/hexanes,1:10 to 1:2) to yield the title compound (138 mg; 61%) with thefollowing physical properties: mp 166-167° C.; MS (M)⁺: 511, 5.13.

Example 130

(4-bromo-3-chlorophenyl)[5-(4-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions descried in Example 1 were repeated using4-ethoxybenzenecarbohydrazide (145 mg; 0.80 mmol) and4-bromo-3-chlorobenzenisothiocyanate (200 mg; 0.80 mmol) to yieldN-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)(4-ethoxyphenyl)carboxamide(314 mg; 92%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.2 mL) were used to yield the title compound(205 mg; 68%) with the following physical properties: mp 225-226° C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.78 (1H, s), 8.13 (1H, d), 7.78 (2H, d),7.71 (1H, d), 7.43 (1H, dd), 7.06 (2H, d), 4.10 (2H, q), 1.35 (3H, t).

Example 131-132

(3-bromophenyl)[5-(3-nitropheny)(1,3,4-thiadiazol-2-yl)]benzylamine and

2-[aza(3-bromophenyl)methylene]-5-3-nitrophenyl)-3-benzyl-1,3,4-thiadiazoline

The reaction described in Example 8 was repeated using(3-bromophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine (150 mg;0.40 mmol), potassium tert-butoxide (0.40 mL; 0.40 mmol) and benzylbromide (0.057 mL; 0.47 mmol) to yield2-[aza(3-bromophenyl)methylene]-5-(3-nitrophenyl)-3-benzyl-1,3,4-thiadiazoline(46 mg; 24%) with the following physical properties: R_(f): 0.50hexanes/ethyl acetate, 2/1); mp 133-134° C.;

¹H NMR (300 MHz, d₁-CDCl₃): δ 8.49 (1H, s), 8.25 (1H, d), 7.93 (1H,d),7.60 (1H, t), 7.51 (2H, d), 7.41-7.33 (3H, m), 7.26-7.23 (3H, m),7.06-7.03 (1H, m), 5.40 (2H,s); and(3-bromophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl))benzylamine(136 mg; 73%) with the following physical properties: R_(f): 0.35(hexanes/ethyl acetate, 2/1); MS (M)⁺: 466, 468;

¹H NMR (300 MHz, d₁-CDCl₃): δ 8.53 (1H, s), 8.24 (1H, d), 8.18 (1H, d),7.60 (1H, t), 7.51-7.47 (2H, m), 7.34-7.23 (7H,m), 5.26 (2H, s).

Example 133

[5-(3,4-dimnethoxyphenyl)(1,3,4-thiadiazol-2-yl)](4-bromo-3-chlorophenyl)amine

The reactions described in Example 1 were repeated using1,2-dimethoxybenzene-4-carbohydrazide (158 mg; 0.80 mmol) and4-bromo-3-chlorobenzenisothiocyanate (200 mg; 0.80 mmol) to yield(3,4-dimethoxyphenyl)-N-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)carboxamide(330 mg; 93%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.3 mL) were used to yield the title compound(218 mg; 70%) with the following physical properties: mp 251.5-252.5°C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.81 (1H, s), 8.14 (1H, d), 7.72 (1H, d),7.45-7.35 (3H, m), 7.07 (1H, d).

Example 134

4-{5-[(4-bromo-3-chlorophenyl)amino]-1,3,4-thiadiazol-2-yl}benzene-1,2-diol

The reactions described in Example 1 were repeated using2H-benzo[d]1,3-dioxolane-5-carbohydrazide (145 mg; 0.80 mmol) and4-bromo-3-chlorobenzenisothiocyanate (200 mg; 0.80 mmol) to yield2H-benzo[3,4-d]1,3-dioxolan-5-yl-N-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)carboxamide(302 mg; 88%) in the first step with the following physical properties:

¹H NMR (300 MHz, di-CDCl₃): δ 10.43 (1H, s), 9.95 (1H, s), 9.87 (1H, s),7.83 (1H, s), 7.71 (1H, d), 7.54 (1H, d), 7.48-7.46 (2H, m), 7.04 (1H,d), 6.12 (2H, s).

In the second step, all the crude product and sulfuric acid (0.4 mL)were used to yield the title compound (190 mg; 68%) with the followingphysical properties: mp 220° C. decomposed; ¹H NMR (300 MHz d₆-DMSO): δ10.73 (1H, s), 9.56 (1H, s), 9.42 (1H, s), 8.13 (1H, d), 7.71 (1H, d),7.41 (1H, dd), 7.30 (1H, d), 7.11 (1H, dd), 6.83 (1H, d).

Example 135

(4-bromo-3-chlorophenyl)[5-3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 1 were repeated using1-phenoxybenzene-3-carbohydrazide (184 mg; 0.80 mmol) and4-bromo-3-chlorobenzenisothiocyanate (200 mg; 0.80 mmol) to yieldN-({[(4-bromo-3-chlorophenyl)amino]thioxomethylamino)(3-phenoxyphenyl)carboxamide (365 mg; 95%) of in the first step.In the second step, all the crude product and sulfuric acid (0.4 mL)were used to yield the title compound (286 mg; 81%) with the followingphysical properties: mp 216-217° C.; MS (M)⁺: 457, 459, 461.

Example 136

(4-{5-[(4-bromo-3-chlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)diethylamine

The reactions described in Example 1 were repeated using4-(diethylamino) benzenecarbohydrazide (167 mg; 0.80 mmol) and4-bromo-3-chlorobenzenisothiocyanate (200 mg; 0.80 mmol) to yield[4-(diethylamino)phenyl]-N-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)carboxamide (319 mg; 88%) in the first step. Inthe second step, all the crude product and sulfuric acid (0.4 mL) wereused to yield the title compound (226 mg; 74%) with the followingphysical properties: mp 232-233° C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.68 (1H, s), 8.13 (1H, d), 7.70 (1H, d),7.63 (2H, d), 7.40 (1H, dd), 6.74 (2H, d), 3.40 (4H, q), 1.12 (6H, t).

Example 137

(4-bromo-3-chlorophenyl)[5-(3-methylphenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 1 were repeated using1-methylbenzene-3-carbohydrazide (167 mg; 0.80 mmol) and4-bromo-3-chlorobenzenisothiocyanate (121 mg; 0.80 mmol) to yieldN-({[(4-bromo-3-chlorophenyl)amino]thioxomethyl}amino)(3-methylphenyl)carboxamide(306 mg; 93%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.3 mL) were used to yield the title compound(230 mg; 79%) with the following physical properties: mp 230-231° C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.87 (1H, s), 8.14 (1H, s), 7.74-7.66 (3H,m), 7.46-7.38 (2H, m), 7.33 (1H, d), 2.39 (3H, s).

Example 138

(naphthylmethyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 1 were repeated using1-nitrobenzene-3-carbohydrazide (245 mg; 1.35 mmol) andnaphthylmethanisothiocyanate (270 mg; 1.35 mmol) to yieldN-({[(naphthylmethyl)amino]thioxomethyl}amino)(3-nitrophenyl)carboxamide(482 mg; 94%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.5 mL) were used to yield the title compound(244 mg; 53%) with the following physical properties: mp 150-151° C.;

¹H NMR (300 MHz, d₆-DMSO): δ 8.72 (1H, t), 8.51 (1H, s), 8.27 (1H, d),8.18 (1H, d), 8.14 (1H, d), 7.99 (1H, d), 7.91 (1H, d), 7.77 (1H, t),7.64-7.48 (4H, m), 5.05 (2H, d).

Example 139

(3,4-dichlorophenyl)[5-(4-phenylphenyl)(1,3,4-thiadiazol-2-yl)]amine

The reactions described in Example 1 were repeated using1-phenylbenzene-4-carbohydrazide (200 mg; 0.94 mmol) and3,4-dichlorobenzenisothiocyanate (192 mg; 0.94 mmol) to yieldN-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)(4-phenylphenyl)carboxamide(360 mg; 92%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.4 mL) were used to yield the title compound(283 mg; 82%) with the following physical properties: mp 305.5-306.5°C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.92 (1H, s), 8.16 (1H, d), 7.97 (2H, d),7.84 (2H, d), 7.74 (2H, d), 7.62 (1H, d), 7.54-7.49 (3H, m), 7.45-7.42(1H, m).

Example 140

(4-{5[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl}lphenyl)dimethylamine

The reactions described in Example 1 were repeated using4-(dimethylamino) benzenecarbohydrazide (200 mg; 1.1 mmol) and3,4-dichlorobenzenisothiocyanate (228 mg; 1.1 mmol) to yield[4-(dimethylamino)phenyl]-N-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)carboxamide(404 mg; 94%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.4 mL) were used to yield the title compound(368 mg; 96%) with the following physical properties: mp 298.5-299.5°C.;

¹HNMR (300 MHz, d₆-DMSO): δ 10.70 (1H, s), 8.13 (1H, s), 7.66 (2H, d),7.58 (1H, d), 7.48 (1H, d), 6.79 (2H, d), 2.99 (6H, s).

Example 141

(3,4-dichlorophenyl)[5-(4-methylthiophenyl)(1,3,4-thiadiazol-2-yl)]amineThe reactions described in Example 1 were repeated using1-methylthiobenzene-4-carbohydrazide (200 mg; 1.1 mmol) and3,4-dichlorobenzenisothiocyanate (224 mg; 1.1 mmol) to yieldN-({[(3,4-dichlorophenyl)amino]thioxomethyl}amino)(4-methylthiophenyl)carboxamide(358 mg; 84%) in the first step. In the second step, all the crudeproduct and sulfuric acid (0.4 mL) were used to yield the title compound(251 mg; 74%) with the following physical properties: mp 247.5-248.5°C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.86 (1H, s), 8.13 (1H, d), 7.80 (2H, d),7.60 (1H, d), 7.49 (1H, dd), 7.38 (2H, d), 2.54 (3H, s).

Example 142

methyl3-({2-[aza(3,4-dichlorophenyl)methylene]-5-(3-ethoxyphenyl)-1,3,4-thiadiazolin-3-yl}methyl)benzoate

The reactions described in Example 1 were repeated using1-ethoxybenzene-3-carbohydrazide (1.000 g; 5.6 mmol) and3,4-dichlorobenzenisothiocyanate (1.133 g; 5.6 mmol) to yieldN-({[(3,4-dichlorophenyl)amino]thioxomethyl}lamino)(3-ethoxyphenyl)carboxamide(1.922 g; 90%) in the first step. In the second step, all the crudeproduct and sulfuric acid (2.0 mL) were used to yield the title compound(1.738 g; 95%) with the following physical properties:

¹H NMR (300 MHz, d₆-DMSO): δ 10.88 (1H, s), 8.15 (1H, d), 7.61 (1H, d),7.51 (1H, dd), 7.44-7.39 (3H, m), 7.10-7.07 (1H, m), 4.11 (2H, q), 1.37(3H, t).

Example 143-144

methyl3-({2-[aza(3,4-dichlorophenyl)methylene]-5-(3-ethoxyphenyl)-1,3,4-thiadiazolin-3-yl}methyl)benzoate

and

methyl3-({(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amino}methyl)benzoate

The reaction described in Example 8 was repeated using(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(120 mg; 0.33 mmol), potassium tert-butoxide (33 mL; 0.33 mmol) andmethyl 3-(bromomethyl)benzoate (90 mg; 0.39 mmol) to yield methyl3-({2-[aza(3,4-dichlorophenyl)methylene]-5-(3-ethoxyphenyl)-1,3,4-thiadiazolin-3-yl}methyl)benzoate(24 mg; 14%) with the following physical-properties: R_(f): 0.55(hexanes/ethyl acetate, 2/1); mp 87-88° C.; MS (M)⁺: 513, 515; andmethyl3-({(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amino}methyl)benzoate(128 mg; 75%) with the following physical properties: R_(f): 0.34(hexanes/ethyl acetate, 2/1); MS (M)⁺: 513, 515.

Example 145

(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)][(4-phenylphenyl)methyl]amineethyl)benzoate

The reaction described in Example 8 was repeated using(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(120 mg; 0.33 mmol), potassium tert-butoxide (0.33 mL; 0.33 mmol) and4-(bromomethyl)-1-phenylbenzene (97 mg; 0.39 mmol) to yield the titlecompound (132 mg; 75%) with the following physical properties: MS(M+H)⁺: 532, 534;

¹H NMR (300 MHz, d₁-CDCl₃): δ 7.58-7.26 (14H, m), 7.21 (1H, dd),6.96-6.91 (1H, m), 5.26 (2H, s), 4.07 (2H, q), 1.42 (3H, t).

Example 146

1-({2-[aza(3,4-dichlorophenyl)methylene]-5(3-ethoxyphenyl)(1,3,4-thiadiazolin-3-yl)}methyl)-3-methoxybenzene

The reaction described in Example 8 was repeated using(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(120 mg; 0.33 mmol), potassium tert-butoxide (0.33 mL; 0.33 mmol) and3-(bromomethyl)-1-methoxybenzene (79 mg; 0.39 mmol) to yield1-({2-[aza(3,4-dichlorophenyl)methylene]-5-(3-ethoxyphenyl)(1,3,4-thiadiazolin-3-yl)}methyl)-3-methoxybenzene(21 mg; 13%) with the following physical properties: R_(f): 0.54(hexanes/ethyl acetate, 2/1); mp 89-90° C.; MS (M)⁺: 485, 487; and(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)][(3-methoxyphenyl)methyl]amine(108 mg; 67%) with the following physical properties: R_(f): 0.38(hexanes/ethyl acetate, 2/1); MS (M)⁺: 485, 487.

Example 147

(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)][(3-nitrophenyl)methyl]amine

The reaction described in Example 8 was repeated using(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(120 mg; 0.33 mmol), potassium tert-butoxide (0.33 mL; 0.33 mmol) and3-(bromomethyl)-1-nitrobenzene (85 mg; 0.39 mmol) to yield3-{2-[aza(3,4-dichlorophenyl)methylene]-3-[(3-nitrophenyl)methyl](1,3,4-thiadiazolin-5-yl)}-1-ethoxybenzene(30 mg; 18%) with the following physical properties: R_(f): 0.53(hexanes/ethyl acetate, 2/1); mp 114-115° C.; MS (M)⁺: 500, 502; and(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)][(3-nitrophenyl)methyl]amine(98 mg; 59%) with the following physical properties: R_(f): 0.30(hexanes/ethyl acetate, 2/1); MS (M)⁺: 500, 502;

¹H NMR (300 MHz, di-CDCl₃): δ 8.18 (1H, s), 8.16 (1H, d), 7.78 (1H, d),7.55-7.49 (3H, m), 7.38 (1H, s), 7.32-7.19 (3H, m), 6.95 (1H, d), 5.33(2H, s), 4.07 (2H, q), 1.42 (3H, t).

Example 148-149

3-{2-[aza(3,4-dichlorophenyl)methylene]-3-(2-naphthylmethyl)(1,3,4-thiadiazolin-5-yl)-1-ethoxybenzene

and

(3,4-dichlorophenyl)[5-3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)](2-naphthylmethyl)amine

The reaction described in Example 8 was repeated, but using of(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine(120 mg; 0.33 mmol), potassium tert-butoxide (0.33 mL; 0.33 mmol) and2-(bromomethyl)naphthalene (87 mg; 0.39 mmol) to yield3-{2-[aza(3,4-dichlorophenyl)methylene]-3-(2-naphthylmethyl)(1,3,4-thiadiazolin-5-yl)}-1-ethoxybenzene(23 mg; 14%) with the following physical properties: R_(f): 0.52(hexanes/ethyl acetate, 2/1); mp 74-75° C.; MS (M)⁺: 505, 507; and(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)](2-naphthylmethyl)amine(110 mg; 66%) with the following physical properties: R_(f): 0.43(hexanes/ethyl acetate, 2/1); mp 43-44° C.; MS (M)⁺: 505, 507.

Example 150

(3,4-dichlorophenyl)(5-[3-(4-methoxyphenoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated, but using[3-(4-methoxyphenoxy)phenyl]formaldehyde (193 mg; 0.85 mmol) and theproduct from Procedure D (200 mg; 0.85 mmol) to yield({(1E)-1-aza-2-[3-(4-methoxyphenoxy)phenyl]vinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thione(326 mg; 86%) in the first step. In the second step, all the crudeproduct and iron (m) chloride hexahydrate (593 mg; 2.20 mmol) were usedto yield the title compound (158 mg; 45/o) with the following physicalproperties: mp 198-199° C.; MS (M)⁺: 443, 445.

Example 151

(3,4-dichlorophenyl){5-[3-(4-methylphenoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using[3-(4-methylphenoxy)phenyl]formaldehyde (180 mg; 0.85 mmol) and theproduct from Procedure D (200 mg; 0.85 mmol) to yield({(1E)-1-aza-2-[3-(4-methylphenoxy)phenyl]vinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thione(322 mg; 88%) in the first step. In the second step, all the crudeproduct and of iron (III) chloride hexahydrate (607 mg; 2.25 mmol) wereused to yield the title compound (166 mg; 52%) with the followingphysical properties: mp 210-211° C.; MS (M)⁺: 427, 429.

Example 152

(3,4-dichlorophenyl){5-[3-(3,5-dichlorophenoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using[3-(3,5-dichlorophenoxy) phenyl]formaldehyde (226 mg; 0.85 mmol) and theproduct from Procedure D (200 mg; 0.85 mmol) to yield({(1E)-1-aza-2-[3-(3,5-dichlorophenoxy)phenyl]vinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thione(366 mg; 89%) in the first step. In the second step, all the crudeproduct and iron (11 chloride hexahydrate (612 mg; 2.26 mmol) were usedto yield the title compound (192 mg; 53%) with the following physicalproperties: mp 242-243° C.; MS M)⁺: 481, 483, 485.

Example 153

(3,4-dichlorophenyl)(5-[3-(3,4-dichlorophenoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

The reactions described in Example 2 were repeated using[3-(3,4-dichlorophenoxy)phenyl]formaldehyde (226 mg; 0.85 mmol) and theproduct from Procedure D (200 mg; 0.85 mmol) to yield({(1E)-1-aza-2-[3-(3,4-dichlorophenoxy)phenylvinyl}amino)[(3,4-dichlorophenyl)amino]methane-1-thione(292 mg; 71%) in the first step. In the second step, all the crudeproduct and iron (I) chloride hexahydrate (488 mg; 1.81 mmol) were usedto yield the title compound (20 mg; 7%) with the following physicalproperties: mp 189-190° C.; MS (M)⁺: 481, 483, 485.

Example 154

(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amine

The reactions described in Example 2 were repeated using{3-[3-(trifluoromethyl)phenoxy]phenyl}formaldehyde (226 mg; 0.85 mmol)and the product from Procedure D (200 mg; 0.85 mmol) to yield[((1E)-1-aza-2-{3-[3-(trifluoromethyl)phenoxy]phenylvinyl)amino][(3,4-dichlorophenyl)amino]methane-1-thione(282 mg; 69%) in the first step. In the second step, all the crudeproduct and iron (III) chloride hexahydrate (472 mg; 1.75 mmol) wereused to yield the title compound (156 mg; 56%) with the followingphysical properties: mp 212-213° C.; MS (M)⁺: 481, 483.

Example 155

(5-(2H-benzo[d]1,3-dioxolan-5-yl)(1,3,4-thiadiazol-2-yl))(3,4-dichlorophenyl)amine

The reactions described in Example 2 were repeated using2H-benzo[3,4-d]1,3-dioxolan-5-ylformaldehyde (127 mg; 0.85 mmol) and theproduct from Procedure D (200 mg; 0.85 mmol) to yield[((1E)-2-(2H-benzo[3,4-d]1,3-dioxolan-5-yl)-1-azavinyl)amino][(3,4-dichlorophenyl)amino]methane-1-thione (274 mg; 88%) in the first step. In the secondstep, all the crude product and iron (m) chloride hexahydrate (604 mg;2.23 mmol) were used to yield the title compound (120 mg; 50%) with thefollowing physical properties: mp 271-272° C.;

¹H NMR (300 MHz, d₆-DMSO): δ 10.82 (1H, s), 8.13 (1H, d), 7.59 (1H, d),7.49 (1H, dd), 7.44 (1H, s), 7.36 (1H, d), 7.05 (1H, d), 6.13 (2H, s).

Example 156

Methyl4-{[(3,4-dichlorophenyl)(5-{3-[3-trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amino]methyl}benzoate

As described in Example 8, the title compound was prepared from(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)-phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amine(300 mg) and methyl-(4-(bromomethyl)benzoate (210 mg). The titlecompound had the following physical properties: MS 629.96.

Example 157

4-{[(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}-(1,3,4-thiadiazol-2-yl))amino]methyl}benzoicacid

As described in Example 7, the title compound was prepared from methyl4-{[(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amino]methyl}benzoate(50 mg) and sodium hydroxide (0.8 mL; 2.5M). The title compound had thefollowing physical properties: mp 114-116° C. (from 4/1 Hexanes/EthylAcetate), MS 615.93.

Example 158

(3,4-dichlorophenyl)(5-{3-[3-(oxymethyl)phenoxy]phenyl)(1,3,4-thiadiazol-2-yl))amine

The reaction described in Procedure B was repeated using 3-hydroxybenzylalcohol (1.5 g) and 3-bromobenzaldehyde (2.7 g). In the second step,using a procedure similar to that described in Example 2,{3-[3-hydroxymethyl)phenoxy]phenyl}formaldehyde (500 mg), semicarbazide(400 mg) and FeCl₃6H₂O (120 mg) in ethanol (10 mL) were used to yieldthe title compound with the following physical properties: mp 128-130°C., MS 443.90.

Example 159

[(4-methylphenyl)sulfonyl](4-{[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amino}phenyl)amine

As described in Example 1,(4-aminophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine wasprepared from (tert-butoxy)-N-(4-isothiocyanatophenyl)carboxamide (200mg) and N-amino(3-nitrophenyl)-carboxamide (130 mg). The Boc protectinggroup is lost during the cyclization reaction.

As described in Example 10 (with sulfonyl chloride in place of acylchloride), the title compound was prepared from(4-{[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amino}phenyl)amine (100mg) and 4-toluenesulfonyl chloride (96 mg). The title compound had thefollowing physical properties: mp 255-257° C.

Example 160

(3,4-dichlorophenyl){5-[3,5-bis(phenylmethoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

As described in Example 2, the title compound was prepared from[3,5-bis(phenylnethoxy)phenyl]formaldehyde (400 mg) and[(3,4-dichloro-phenyl)amino]hydrazinomethane-1-thione (290 mg). Thetitle compound had the following physical properties: mp 212-214° C.;LC-MS: 533.99.

Example 161

3-{5-[(3-bromophenyl)amino]-1,3,4-thiadiazol-2-yl}benzoic acid

As described in Example 2, the title compound was prepared from3-carbonylbenzoic acid (70 mg) and[(3-bromophenyl)amino]hydrazinomethane-1-thione (100 mg). The titlecompound had the following physical properties: mp 270-272° C.

Example 162

(5-benzo[c]1,2,5-oxadiazol-5-yl(1,3,4-thiadiazol-2-yl))(3,4-dichlorophenyl)amine

As described in Example 1, the title compound was prepared from3,4-dichlorobenzenisothiocyanate (120 mg) andN-aminobenzo[3,4-c]1,2,5-oxadiazol-5-ylcarboxamide (88 mg). The titlecompound had the following physical properties: mp 315-317° C.; LC-MS364.1.

Example 163

[(3-phenylmethoxy)phenyl](5-{3-[3-trifluoromethyl)phenoxy]-phenyl)(1,3,4-thiadiazol-2-yl)}amine

As described in Example 2, the title compound was prepared from{3-[3-(trifluoromethyl)phenoxy]phenyl}formaldehyde (490 mg) and[({3-phenylmethoxy}phenyl)amino]hydrazinomethane-1-thione (500 mg). Thetitle compound had the following physical properties: mp 150-152° C.;LC-MS: 520.02.

Example 164

3-{3-[5-(3,4-Dichloro-phenylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl-phenoxy}-benzoicacid

3-{3-[5-(3,4-Dichloro-phenylimino)-4-methyl4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoicacid methyl ester: The title compound was prepared using the proceduredescribed in Example 8 from3-{3-[5-(3,4-Dichloro-phenylamino)-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoicacid methyl ester (0.32 mmols, 150 mg), potassium tert-butoxide (0.32mL, 1 M, 0.32 mmol) and methyl iodide (3.2 mmol, 0.2 mL). Yield: 54 mg(350/0). ¹H NMR (300 MHz, d₆-DMSO): δ 7.78-7.07 (11H, m), 3.84 (3H, s),3.69 (3H, s).

The title compound was prepared using the procedure described in Example7 from3-{3-[5-(3,4-Dichloro-phenylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-phenoxy)-benzoicacid methyl ester (0.03 mmols, 16 mg) and LiOH (0.03 mmol, 7.8 mg).Yield: 12 mg (85%). mp 193-196° C.

¹H NMR (300 MHz, d₁-CDCl₃): δ 7.89 (1H, d), 7.70 (1H, s), 7.50-7.21 (7H,m), 7.07 (1H, d), 6.95 (1H, d), 3.78 (3H, s).

Example 165

4-{N′-[1-(3-{5-[3-(3-Trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-2-ylamino}-phenyl)-ethylidene]-hydrazino}-benzoicacid

N-({[(3-acetylphenyl)amino]thioxomethyl}amino){3-[3(trifluoromethyl)phenoxy]phenyl}carboxamide:The title compound was prepared using the procedure described in Example1 from 3-(3-Trifluoromethyl-phenoxy)-benzoic acid hydrazide (1 mmol, 300mg) and 1-(3-Isothiocyanato-phenyl)-ethanone (1 mmol, 180 mg).

1-(3-{5-[3-(3-Trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-2-ylamino}-phenyl)ethanonewas prepared using the procedure described in Example 1 fromN-({[(3-acetylphenyl)amino]thioxomethyl}amino){3-[3(trifluoromethyl)phenoxy] phenyl}carboxamide and sulfuric acid (0.4mL). Yield: 158 mg (35% from first step). mp 130-133° C.

¹H NMR (300 MHz, d, —CDCl₃): δ 9.67 (1H, s), 8.09 (1H, s), 7.75-7.20(10H, in), 7.10 (1H, d), 2.65 (3H, s).

A solution of1-(3-{5-[3-(3-Trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-2-ylamino}-phenyl)-ethanone(0.18 mmol, 80 mg) and 4-Hydrazino-benzoic acid (0.18 mmol, 27 mg) indry ethanol (5 mL) under nitrogen refluxed overnight. After cooling toroom temperature, the mixture was filtered and the solid washed byethanol, 1N HCl (aqueous), water and hexanes to give the title compoundas a light brown solid (60 mg, 57%); mp 277.5-279° C. LCMS (M+H) 589.9;(M−H) 588.0.

Example 166

4-({[5-(3-phenoxyphenyl)-1,3,4-thiadiazol-2-yl]amino}methyl)benzoic acid

A solution of the product from Procedure D (3-phenoxybenzaldehyde) (1 g,5.04 mmol) and methyl 4-(isocyanate)benzoate (1.04 g, 5.04 mmol) in dryEthanol (25 mL) under Argon was refluxed for two hours. After cooling toroom temperature, the mixture was filtered and the solid washed byethanol.

The solid was suspended in dry ethanol (20 mL) and iron (III) chloridehexahydrate (5.7 mmol, 1.54 g) was added. The reaction mixture wasrefluxed for two more hours, then cooled to room temperature. The solidwas collected by filter and washed by ethanol, then crystallized fromethyl acetate/hexane yielded 1.36 g (65%) of methyl4-({[5-(3-phenoxyphenyl)-1,3,4-thiadiazol-2-yl]amino}methyl)benzoate.

A solution of methyl4-({[5-(3-phenoxyphenyl)-1,3,4-thiadiazol-2-ylamino}methyl)benzoate(1.36 g, 3.26 mmol) and LiOH (1.96 g, 3.5 mmol) in 10 mL of a mixture ofH₂O/MeOH/THF (6:2:2) was stirred at room temperature for two hours. Thesolvent was removed and the residue was purified using flashchromatography on silica gel. Eluting with chloroform/methanol (91:10)provide a white solid (1.16 g, 850%) of4-({[5-(3-phenoxyphenyl)-1,3,4-thiadiazol-2-yl]amino}methyl)benzoicacid.

MS (SSQ 7000): M+=404. Column: Betasil C18 5 μm 50×3 mm Solvent A:Water+0.01% AcOH; Solvent B: CAN+0.1% AcOH M.P: 192-195° C.

Example 167

N-[4-({(3,4-dichlorophenyl)[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amino}methyl)phenyl]methanecarboxylic acid.

Following the procedure described in Example 8, the methyl ester of thetitle compound was prepared from 0.17 g of(3,4-dichlorophenyl)[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amineand 0.11 g of methyl {N-[4-(bromomethyl)phenyl]carbamoyl}-formate.

This ester was subjected to the procedure described in Example 7,yielding the title compound from 0.11 g of methyl{N-[4-({(3,4-dichlorophenyl)[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amino}methyl)phenyl]carbamoyl}formateand 2.0 mL of 2.5M lithium hydroxide, with the following physicalproperties: mp 198-200° C. (from 2/1 Hexanes/Ethyl Acetate), LC-MS 589.

Example 168

4-({(3,4-dichlorophenyl)[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}methyl)benzoicacid.

Following the procedure described in Example 8, the methyl ester of thetitle compound was prepared from 0.40 g of(3,4-dichlorophenyl)[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amine and 0.23g of methyl-(4-(bromomethyl)benzoate.

This ester was subjected to the procedure described in Example 7,yielding the title compound from 0.30 g of methyl4-({(3,4-dichlorophenyl)[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}methyl)benzoateand 2.0 mL of 2.5 M lithium hydroxide, with the following physicalproperties: mp 202-204° C. (from 4/1 Hexanes/Ethyl Acetate), LC-MS 529.

Example 169

N-(3-([(3,4-dichlorophenyl)(5-{3-[3(trifluoromethyl)phenoxy}phenyl)-(1,3,4-thiadiazol-2-yl))amino]methyl}phenyl)methanecarboxylicacid

Following the procedure described in Example 8, the methyl ester of thetitle compound was prepared from 0.3 g of(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amineand 0.2 g of methyl {N-[4-(bromomethyl)phenyl]carbamoyl}formate.

This ester was subjected to the procedure described in Example 7,yielding the title compound from 0.11 g ofmethyl[N-(4-{[(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amino]methyl}phenyl)carbamoyl]formateand 0.2 mL 2.5M lithium hydroxide, with the following physicalproperties: mp 172-174° C. (from 4/1 Hexanes/Ethyl Acetate), MS 659.4[M+].

Example 170

2-{4-[(2-[aza(3,4-dichlorophenyl)methylene]-5-{3-[3-(trifluoromethyl)phenoxy]phenyl}-1,3,4-thiadiazolin-3-yl)methyl]phenyl}aceticacid.

Following the procedure described in Example 8, the methyl ester of thetitle compound was prepared from 0.30 g of(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amineand 0.15 g of methyl-(4-(bromomethyl)benzoate.

This ester was subjected to the procedure described in Example 7,yielding the title compound from 0.013 g of methyl2-(4-{[(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)phenoxyphenyl}(1,3,4-thiadiazol-2-yl))amino]methyl}phenyl)acetateand 0.04 mL of 2.5M lithium hydroxide, with the following physicalproperties: mp 136-138° C. (from 4/1 Hexanes/Ethyl Acetate), MS 630.5[M+].

Example 171

4-{5-[3-3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]-1,2,3,4-tetrazoyl}butanoic acid

3-(3-{5-[3,4-dichlorophenylamino]-1,3,4-thiadiazol-2-yl}phenoxy)benzenecarbonitrile, 3.2 mmol, was dissolved in dry DMF. Sodium azide,9.5 mmol, and ammonium chloride, 9.5 mmol, were added and the mixturewas stirred at 115° C. for 24 hours. The mixture was cooled to roomtemperature and recharged with 5 mmol of sodium azide/ammonium chlorideand heated at 115° C. for 6 hours. The mixture was then cooled to roomtemperature and applied directly to silica gel chromatography,hexane/acetone (4/1) to yield 1.2 g of pure(3,4-Dichlorophenyl)-(5-{3-[3-(2H-tertazol-5-yl)-phenoxy]-phenyl}-[1,3,4]thiadiazol-2-yl)-amine(78%).

(3,4-Dichlorophenyl)-(5-{3-[3-(2H-tertazol-5-yl)-phenoxy]-phenyl}-[1,3,4]thiadiazol-2-yl)-amine,0.09 mmol, was dissolved in ˜1 mL acetone/DMF (1/1). Triethylamine, 0.12mmol, and 4-Iodo-methyl butyrate, 0.1 mmol, were added and heated to 80°Celsius for two hours. The residue was applied directly to silica gelchromatography. The pure product was hydrolyzed in lithiumhydroxide/THF/Methanol (2/1/1). The solution was then neutralized with1M HCl (aq). The crude product was collected by filtration, washingseveral times with water, followed by hexane, then dried en vacuo. Theproduct was recrystallized from ethanol/water to give 25 mg (48%) of thetitle compound, with the following physical properties: mp 137-142° C.(decomposition); MS (A&A Labs); m/z 568.2/570.2 [M+H].

Example 172

4-({(1E)-1-aza-2-[3-3-(5[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenoxy)phenyl]vinyl}amino)benzoicacid

3-(3-[1,3]dioxalan-2-yl-phenoxy) benzaldehyde, 16.6 mmol, and[(3,4-dichloropheny)amino]hydrazinomethane-1-thione, 16.6 mmol, werecombined in ethanol and heated to reflux for two hours. The solution wascooled to room temperature and the precipitate was collected byfiltration, and washed with hexane (3×). The white solid was slurried inethanol and 3 eq of Fe(III)Cl₃ was added. The slurry was refluxed fortwo hours, cooled and the crude product collected by filtration. Thecrude product was washed (3×) with water followed by hexane. The productwas recrystallized from hot ethanol/water to give 3.2 g of the titlecompound. Yield 39%(isolated).

This product was subjected to 0.1M HCl in methanol at room temperaturefor 18 hours to reveal the aldehyde,3-{3-[5-(3,4-dichloro-phenylamino)-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzaldehyde,which was purified on silica gel; hexane/ethyl acetate (1/1), followedby recrystalization to give 1.7 g of product (60%).

3-{3-[5-(3,4-dichloro-phenylamino)-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzaldehyde0.38 mmol, and 4-carboxy-phenyl hydrazine were combined in ethanol andheated at reflux for 4 hours. Upon cooling the product precipitated andwas washed with water and hexane to give 75 mg (34%) of analyticallypure title compound, with the following physical properties: mp 259-262°C. MS (A&A Labs); m/z 576.5 [M+H].

Example 173

(6Z)-7-[3-(3-{5-[3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenoxy)phenyl]heptanoicacid

[6-(Ethoxycarbonyl)hexyl]triphenylphosphonium bromide, 35 mmol, in 75 mLTBF at 0° C. under an Argon atmosphere was treated with 34 mmol of NaHMDS (2.5M in TBF) and stirred for 30 minutes at room temperature. Themixture was then cooled to 0° C. and 3-(3-[1,3] dioxalan-2-yl-phenoxy)benzaldehyde, 3.5 mmol in 10 mL THF was added via syringe. The ice bathwas removed and the reaction was stirred at room temperature for onehour. The reaction was then diluted with ether and 250 mL of saturatedammonium chloride was added. The aqueous layer was extracted with ether(3×) and the combined organic fraction was washed with brine, dried withMgSO₄, and the solvent removed on a rotovap. The crude compound waspurified by silica gel chromatography (hexane/ethyl acetate) to give 1.2g of product (−9/1) cis/trans. The acetal was hydrolyzed with 1N HCl/ThF(1/9) at room temp for 12 hours. The product was purified by silica gelchromatography to yield 765 mg of the cis isomer,7-[3-(3-Formyl-phenoxy)-phenyl]-hept-6-enoic acid ethyl ester (yield:63%, from 3-(3-[1,3] dioxalan-2-yl-phenoxy) benzaldehyde).

7-[3-(3-Formyl-phenoxy)-phenyl]-hept-6-enoic acid ethyl ester. 0.85mmol, and [(3,4-dichloropheny)amino]hydrazinomethane-1-thione, 0.85mmol, were combined as described in Example 2, followed by hydrolysiswith 0.25M LiOH in THF to give 200 mg of the title compound, yield: 43%,which was recrystallized from ethanol/water, with the following physicalproperties: mp 142-145° C. MS m/z 540.3 [M+H].

Selected compounds of the invention are evaluated for biologicalactivity as inhibitors of tyrosine phosphatase as described previously,and the results are presented in FIG. 1.

In addition, selected compounds of the present invention, identified byexample or compound number, have been evaluated for biological activityas inhibitors of other tyrosine phosphatases as described previously,and the results are as follows: PTP-1B TC-PTP PTP-β CD-45 Compound IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) Example 16 12 30, 30 >100 30 Example135 6 20, 12 >100 20 Example 66 7 20, 30 >100 25 Example 80 7 14,8  >100 80 Example 14 5 12 24 10 Example 7 12 15 31 17 Example 172 0.81.6 30 14 Example 168 1 Example 169 1 Example 171 2 Compound 187 1 1 5 5Compound 188 10 Compound 190 5 Compound 198 4

All patents and patent applications cited in this specification arehereby incorporated by reference as if they had been specifically andindividually indicated to be incorporated by reference.

1. A method of inhibiting protein tyrosine phosphatase activity whichcomprises administering to a mammal an effective amount of a compoundhaving the formula:

or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, hydroxyl, alkoxy, alkylthio,nitro, amino or amido (each unsubstituted or substituted with alkyl,amino, cycloheteroalkyl, cycloalkyl fluoro, aryl, heteroaryl,cycloheteroalkyl, alkylthio, arylthio, cyano, OR′, OC═OR″, C═O—OR′″, orC═O—NR″″R″″); small alkyl (C1-C10) (unsubstituted or substituted withalkyl, amino, cycloheteroalkyl, cycloalkyl fluoro, aryl, heteroaryl,cycloheteroalkyl, alkylthio, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂, arylthio, cyano, OR″, OC═OR″, C═O—OR′″, orC═O—NR″″R″″); phenyl and mono and disubstituted (at positions 3 and 4)phenyl (wherein the phenyl ring is independently substituted with alkyl,trifluoromethyl, mono and di halogen atoms, alkylthio, alkoxy, nitro,cyano, morphilino, cyclohexyl, phenyl, phenolic, dioxymethylene, nitro,acetylamino, OR′, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂); heteroaryl, cycloheteroalkyl and cycloheteroalkyl (eachunsubstituted or substituted with alkyl, halogen, alkylthio, alkoxy, ornitro, OR′, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂,); cycloalkyl (C3-C10) (unsubstituted or substituted withalkyl, fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylalkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂, OR′, OC═OR′, C═O—OR″, or C═O—NR′″ R″″); alkenyl(C1-C10) (unsubstituted or substituted with alkyl, fluoro, aryl,heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio, arylthio,cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂,OR′, OC—OR′, C═O—OR″, or C═O—NR′″R″″); alkadienyl (C1-C10)(unsubstituted or substituted with alkyl, fluoro, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl, alkylthio, arylthio, cyano,P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′,—OC═OR5, —C═O—OR″, C═O—NR′″R″″); cycloalkenyl (C4-C10), unsubstituted orsubstituted with alkyl, fluoro, aryl, heteroaryl, cycloheteroalkyl,cycloheteroalkyl, alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″, C═O—NR′″R″″; bicycloalkyl (C5-C12), unsubstituted or substituted with alkyl,fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio,arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″, C—O—NR′″R″″; tricycloalkyl (C8-C14),unsubstituted or substituted with alkyl, fluoro, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl, alkylthio, arylthio, cyano,P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′,—OC═OR′, —C═O—OR″, C═O—NR′″R″″;  where Each R′ is independently:hydrogen; alkyl (C1-C10), unsubstituted or substituted with alkyl, keto,fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl,cycloheteroalkyl, cyano, aryloxy, cycloalkyl, COOR″, P═O(OR″)₂,CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; aryl, unsubstitutedor substituted with alkyl, keto, fluoro, alkoxy, alkylthio, cyano,aryloxy, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂; heteroaryl, cycloheteroalkyl, cycloheteroalkyl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, cyano, aryloxy, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; cycloalkyl, unsubstituted or substituted withalkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl, cyano, COOR″, P═O(OR″)₂,CH₂P═O(OR″)₂, CF₂P—O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; Each R″ isindependently hydrogen, alkyl (C1-C10), unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl; aryl, unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio; heteroaryl,cycloheteroalkyl, unsubstituted or substituted with alkyl, keto, fluoro,alkoxy, alkylthio; cycloalkyl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl;Each R′″ is independently alkyl (C1-C10), unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; aryl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio; heteroaryl, cycloheteroalkyl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂; cycloalkyl, unsubstituted or substituted with alkyl, keto,fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl, COOR″,P═O(OR″)₂, CH₂P—O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; and EachR″″ is independently alkyl (C1-C10), unsubstituted or substituted withalkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, COOR″, PO(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; aryl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; heteroaryl, cycloheteroalkyl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂; and cycloalkyl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalky,COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; andwherein each of R1, R2 and R3 are linked to their respective core atomsthrough C, N, O or S of the substiuent group, provided that if R2 is tobe linked through O or S, then the core atom S is oxidized.
 2. A methodas recited in claim 1 wherein R1 and R2 are taken together with the coreunit to which they are attached (formula I) to form a heterocyclic grouphaving formula (II) as follows:

wherein R5 is an amino group with two substituents, where onesubstituent is arylcarbonyl, arylmethylcarbonyl, arylsulfonyl,aryldimethyloxycarbonyl, or aryloxymethylcarbonyl, [where the aryl groupis phenyl, benzox[c]1,2,5-oxadiazol-5-yl, 1-furyl, 2-furyl 1-naphthyl or2-naphthyl, unsubstituted or substituted with one or more of thefollowing or their combinations: perfluoroalkyl (C1-C4), alkyl (C1-C4),nitro, alkoxycarbonyl (C1-C4), carboxyl, carboxyalkyl(C1-C4),CF₂P═O(OH)₂, NHCOCOOH, phenoxy (unsubstituted or substituted with alkoxy(C1-C4), CF₂P═O(OH)₂, NHCOCOOH, COOH, and/or halogen), or phenylalkoxy(C1-C4)], hydrogen, CF₂P═O(OH)₂, NHCOCOOH, or a phenyl group[unsubstituted or with one or more of the following substituents orcombinations: hydroxy, halogen, nitro, CF₂P═O(OH)₂, NHCOCOOH, carboxy,carboxyalkyl(C1-C4), carboxyalkylthio (C1-C6), phenyl, alkyl (C1-C10) oralkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH,cycloheteroalkyl), perfluoroalkyl (C1-C4), alkoxycarbonyl (C1-C4),alkylthio (C1-C4), phenylalkoxy (C1-C4), phenylsulfonylamino (eachunsubstituted or substituted on phenyl with alkyl (C1-C4)), phenoxy(unsubstituted or substituted on phenyl with nitro, perfluoroalkyl(C1-C4), carboxymethyl, carboxy, CF₂P═O(OH)₂, NHCOCOOH,alkoxycarbonylmethyl (C1-C4)), carboxyalkyl(C1-C4), phenylalkylthio(C1-C4, unsubstituted or substituted on phenyl with alkoxy (C1-C4),and/or phenyl), aminosulfonyl, alkylaminosulfonyl (C1-C4),dialkylaminosulfonyl (C1-C4 where the two alkyls unsubstituted or form aheteroalicyclic ring)]; and the second substituent on the amino groupforming R5 is hydrogen, alkyl (C1-C10) or alkoxy (C1-C10) (eachunsubstituted or substituted with NR1R2, COOH, CF₂P═O(OH)₂, NHCOCOOH,cycloheteroalkyl), naphthylalkyl (C1-C4), phenylalkyl (C1-C4, with thephenyl group unsubstituted or substituted with phenyl, alkyl (C1-C4),halo, amino, amido, keto, CF₂P═O(OH)₂, NHCOCOOH, alkyl (C1-C10) oralkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH,cycloheteroalkyl), nitro, carboxy, perfluoroalkylthio (C1-C4), halogen,CF₂P═O(OH)₂, NHCOCOOH, 1,2,3-thiadiazolyl, and/or alkoxy carbonyl(C1-C4)), alkyl (C1-C10), cycloalkyl (C4-C8, unsubstituted orsubstituted with alkyl (C1-C4)), or indanyl (unsubstituted orsubstituted with alkyl (C1-C4)).
 3. A method as recited in claim 2wherein R3 is (1) a phenyl group unsubstituted or substituted with oneto three of the following and their combinations: halogen, hydroxy,aryloxy, nitro, carboxylic acid, CF₂P═O(OH)₂, NHCOCOOH, alkyl (C1-C10)or alkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH,cycloheteroalkyl), alkylthio (C1-C4), 2′-hydroxyethoxy,alkoxycarbonylmethoxy (C1-C4), dialkylamino (C1-C4 where the two alkylscan form a heteroalicyclic ring), 2-(dialkylamino)-2-oxoethoxy (C1-C7where the two alkyls can form a heteroalicyclic ring), difluoromethoxy,perfluoroallyl (C1-C4), perfluoroalkylthio (C1-C4), perfluoroalkoxy(C1-C4), 2-carboxyvinyl, alkanoyl (C1-C5), alkoxycarbonyl (C1-C4),alkanoylamino (C1-C8), benzoylamino (unsubstituted or substituted withone or more perfluoroalkyl group (C1-C4) and/or CF₂P═O(OH)₂, NHCOCOOH,),aryl, aryloxy, arylcarbonyl, arylmethoxy, arylmethyl in which the methylgroup is substituted with hydroxyl, O(CH₂)_(n)COOH (n=1-5),S(CH₂)_(n)COOH (n=1-5), (4-carboxy)benzyloxy, (3-carboxybenzyloxy), orthe group ═N—O—CH₂R in which R is carboxyl, alkoxycarbonyl (C1-C4),hydrogen, or phenyl (unsubstituted or substituted with one or morehalogens), or the group ═N—NHAr in which Ar is a phenyl (unsubstitutedor substituted with one or more alkyl groups (C1-C4), and/or a carboxylgroup, and/or CF₂P═O(OH)₂, NHCOCOOH), or the group-Y—(CH₂)_(n)-Z, whereY is O or S, n is 1, 2, or 3, and Z is hydrogen, methyl, branched alkyl(C3-C5), cycloalkyl (C3-C6), phenyl (unsubstituted or substituted withone or more of the following: halogen, trifluoroalkyl, carboxy,alkoxycarbonyl (C1-C4), CF₂P═O(OH)₂, NHCOCOOH, or carboxyl; or (2) apyridylthio group unsubstituted or substituted with one or more halogenand/or one or more nitro groups, methylenedioxyphenyl,benzo[3,4-c]1,2,5-oxadiazol-5-yl, 4-oxo-3-hydroquinazolin-2-yl, or agroup having formula (III) as follows:

in which the imidazole ring is unsubstituted or substituted with one ormore halogens.
 4. A method as recited in claim 1 wherein R1 and R2 aretaken together with the core unit to which they are attached (formula I)to form a heterocyclic group having formula (IV as follows:

wherein R6 and R7 are each independently as defined for R1, R2 and R3.5. A method as recited in claim 1 wherein R1 and R2 are linked throughan aromatic ring, and taken together with the N═CR3—S unit to which theyare attached, form a tricyclic heterocyclic group having formula (V) asfollows:

Where R9, R10 and R11 are each independently as defined for R1, R2 andR3.
 6. A method as recited in claim 1 wherein R1 and R2, taken togetherwith the N═CR3—S unit to which they are attached, form a heterocyclicgroup having formula (VI) as follows:

Wherein R12 and R13 are each independently as defined for R1, R2 and R3.7. A method as recited in claim 1 wherein R1 and R3, taken together withthe N═C—SR2 unit to which they are attached, form a heterocyclic grouphaving formula (VII) as follows:

Wherein R14 and R15 are each independently as defined for R1, R2 and R3.8. A method as recited in claim 1 wherein R1 and R3, taken together withthe N═C—SR2 unit to which they are attached, form a bicylic heterocyclicgroup having formula (VII) as follows:

Wherein R18 and R19 are each independently as defined for R1, R2 and R3.9. A method as recited in claim 1 wherein R1, R2 and R3, taken togetherwith the N═C—S unit to which they are attached, form a bicyclicheterocyclic group having formula (IX) as follows:

Wherein R20, R21 and R22 are each independently as defined for R1, R2and R3.
 10. A method as recited in claim 1 wherein R1, R2 and R3, takentogether with the N═C—S unit to which they are attached, form a bicyclicheterocyclic group having formula (X) as follows:

Where R23 and R24 are each independently as defined for R1, R2 and R3.11. A pharmaceutical composition which comprises an effective amount ofa compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3are each independently selected from H, hydroxyl, alkoxy, alkylthio,nitro, amino or amido (each unsubstituted or substituted with alkyl,amino, cycloheteroalkyl, cycloalkyl fluoro, aryl, heteroaryl,cycloheteroalkyl, alkylthio, arylthio, cyano, OR′, OC═OR″, C═O—OR′″, orC═O—NR″″R″″); small alkyl (C1-C10) (unsubstituted or substituted withalkyl, amino, cycloheteroalkyl, cycloalkyl fluoro, aryl, heteroaryl,cycloheteroalkyl, alkylthio, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂, arylthio, cyano, OR″, OC═OR″, C═O—OR′″, orC═O—NR″″R″″); phenyl and mono and disubstituted (at positions 3 and 4)phenyl (wherein the phenyl ring is independently substituted with alkyl,trifluoromethyl, mono and di halogen atoms, alkylthio, alkoxy, nitro,cyano, morphilino, cyclohexyl, phenyl, phenolic, dioxymethylene, nitro,acetylamino, OR′, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂); heteroaryl, cycloheteroalkyl and cycloheteroallyl (eachunsubstituted or substituted with alkyl, halogen, alkylthio, alkoxy, ornitro, OR′, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂,); cycloalkyl (C3-C10) (unsubstituted or substituted withalkyl, fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkylalkylthio, arylthio, cyano, P—O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂, OR′, OC═OR′, C═O—OR″, or C═O—NR′″R″″); alkenyl(C1-C10) (unsubstituted or substituted with alkyl, fluoro, aryl,heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio, arylthio,cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂,OR′, OC═OR′, C═O—OR″, or C═O—NR′″R″″); alkadienyl (C1-C10)(unsubstituted or substituted with alkyl, fluoro, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl, alkylthio, arylthio, cyano,P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′,—OC═OR5, —C═O—OR″, C═O—NR′″R″″); cycloalkenyl (C4-C10), unsubstituted orsubstituted with alkyl, fluoro, aryl, heteroaryl, cycloheteroalkyl,cycloheteroalkyl, alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂,CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″,C═O—NR′″R″″; bicycloalkyl (C5-C12), unsubstituted or substituted withalkyl, fluoro, aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl,alkylthio, arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″, C═O—NR′″R″″;tricycloalkyl (C8-C14), unsubstituted or substituted with alkyl, fluoro,aryl, heteroaryl, cycloheteroalkyl, cycloheteroalkyl, alkylthio,arylthio, cyano, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂, OR′, —OC═OR′, —C═O—OR″, C═O—NR′″R″″;  where Each R′ isindependently: hydrogen; alkyl (C1-C10), unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl, cyano, aryloxy, cycloalkyl, COOR″,P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; aryl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, cyano, aryloxy, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; heteroaryl, cycloheteroalkyl, cycloheteroalkyl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, cyano, aryloxy, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; cycloalkyl, unsubstituted or substituted withalkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl, cyano, COOR″, P═O(OR″)₂,CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; Each R″ isindependently hydrogen, alkyl (C1-C10), unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, cycloheteroalkyl; aryl, unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio; heteroaryl,cycloheteroalkyl, unsubstituted or substituted with alkyl, keto, fluoro,alkoxy, alkylthio; cycloalkyl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl;Each R′″ is independently alkyl (C1-C10), unsubstituted or substitutedwith alkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; aryl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio; heteroaryl, cycloheteroalkyl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂; cycloalkyl, unsubstituted or substituted with alkyl, keto,fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalkyl, COOR″,P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; and EachR″″ is independently alkyl (C1-C10), unsubstituted or substituted withalkyl, keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl,cycloheteroalkyl, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂,NHCOCOOR″, CH(COOR″)₂; aryl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂,CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; heteroaryl, cycloheteroalkyl,unsubstituted or substituted with alkyl, keto, fluoro, alkoxy,alkylthio, COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″,CH(COOR″)₂; and cycloalkyl, unsubstituted or substituted with alkyl,keto, fluoro, alkoxy, alkylthio, aryl, heteroaryl, cycloheteroalky,COOR″, P═O(OR″)₂, CH₂P═O(OR″)₂, CF₂P═O(OR″)₂, NHCOCOOR″, CH(COOR″)₂; andwherein each of R1, R2 and R3 are linked to their respective core atomsthrough C, N, O or S of the substiuent group, provided that if R2 is tobe linked through O or S, then the core atom S is oxidized.
 12. Apharmaceutical composition as recited in claim 11 wherein R1 and R2 aretaken together with the core unit to which they are attached (formula I)to form a heterocyclic group having formula (II) as follows:

wherein R5 is an amino group with two substituents, where onesubstituent is arylcarbonyl, arylmethylcarbonyl, arylsulfonyl,aryldimethyloxycarbonyl, or aryloxymethylcarbonyl, [where the aryl groupis phenyl, benzox[c]1,2,5-oxadiazol-5-yl, 1-furyl, 2-furyl 1-naphthyl or2-naphthyl, unsubstituted or substituted with one or more of thefollowing or their combinations: perfluoroalkyl (C1-C4), alkyl (C1-C4),nitro, alkoxycarbonyl (C1-C4), carboxyl, carboxyalkyl(C1-C4),CF₂P═O(OH)₂, NHCOCOOH, phenoxy (unsubstituted or substituted with alkoxy(C1-C4), CF₂P═O(OH)₂, NHCOCOOH, COOH, and/or halogen), or phenylalkoxy(C1-C4)], hydrogen, CF₂P═O(OH)₂, NHCOCOOH, or a phenyl group[unsubstituted or with one or more of the following substituents orcombinations: hydroxy, halogen, nitro, CF₂P═O(OH)₂, NHCOCOOH, carboxy,carboxyalkyl(C1-C4), carboxyalkylthio (C1-C6), phenyl, alkyl (C1-C10) oralkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH,cycloheteroalkyl), perfluoroalkyl (C1-C4), alkoxycarbonyl (C1-C4),alkylthio (C1-C4), phenylalkoxy (C1-C4), phenylsulfonylamino (eachunsubstituted or substituted on phenyl with alkyl (C1-C4)), phenoxy(unsubstituted or substituted on phenyl with nitro, perfluoroalkyl(C1-C4), carboxymethyl, carboxy, CF₂P═O(OH)₂, NHCOCOOH,alkoxycarbonylmethyl (C1-C4)), carboxyalkyl(C1-C4), phenylalkylthio(C1-C4, unsubstituted or substituted on phenyl with alkoxy (C1-C4),and/or phenyl), aminosulfonyl, alkylaminosulfonyl (C1-C4),dialkylaminosulfonyl (C1-C4 where the two alkyls unsubstituted or form aheteroalicyclic ring)]; and the second substituent on the amino groupforming R5 is hydrogen, alkyl (C1-C10) or alkoxy (C1-C10) (eachunsubstituted or substituted with NR1R2, COOH, CF₂P═O(OH)₂, NHCOCOOH,cycloheteroalkyl), naphthylalkyl (C1-C4), phenylalkyl (C1-C4, with thephenyl group unsubstituted or substituted with phenyl, alkyl (C1-C4),halo, amino, amido, keto, CF₂P═O(OH)₂, NHCOCOOH, alkyl (C1-C10) oralkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH,cycloheteroalkyl), nitro, carboxy, perfluoroalkylthio (C1-C4), halogen,CF₂P═O(OH)₂, NHCOCOOH, 1,2,3-thiadiazolyl, and/or alkoxy carbonyl(C1-C4)), alkyl (C1-C10), cycloalkyl (C4-C8, unsubstituted orsubstituted with alkyl (C1-C4)), or indanyl (unsubstituted orsubstituted with alkyl (C1-C4)).
 13. A pharmaceutical composition asrecited in claim 12 wherein R3 is (1) a phenyl group unsubstituted orsubstituted with one to three of the following and their combinations:halogen, hydroxy, aryloxy, nitro, carboxylic acid, CF₂P═O(OH)₂,—NHCOCOOH, alkyl (C1-C10) or alkoxy (C1-C10) (unsubstituted orsubstituted with NR1R2, COOH, cycloheteroalkyl), alkylthio (C1-C4),2′-hydroxyethoxy, alkoxycarbonylmethoxy (C1-C4), dialkylamino (C1-C4where the two alkyls can form a heteroalicyclic ring),2-(dialkylamino)-2-oxoethoxy (C1-C7 where the two alkyls can form aheteroalicyclic ring), difluoromethoxy, perfluoroalkyl (C1-C4),perfluoroalkylthio (C1-C4), perfluoroalkoxy (C1-C4), 2-carboxyvinyl,alkanoyl (C1-C5), alkoxycarbonyl (C1-C4), alkanoylamino (C1-C8),benzoylamino (unsubstituted or substituted with one or moreperfluoroalkyl group (C1-C4) and/or CF₂P═O(OH)₂, NHCOCOOH,), aryl,aryloxy, arylcarbonyl, arylmethoxy, arylmethyl in which the methyl groupis substituted with hydroxyl, O(CH₂)_(n)COOH (n=1-5), S(CH₂)_(n)COOH(n=1-5), (4-carboxy)benzyloxy, (3-carboxybenzyloxy), or the group═N—O—CH₂R in which R is carboxyl, alkoxycarbonyl (C1-C4), hydrogen, orphenyl (unsubstituted or substituted with one or more halogens), or thegroup ═N—NHAr in which Ar is a phenyl (unsubstituted or substituted withone or more alkyl groups (C1-C4), and/or a carboxyl group, and/orCF₂P═O(OH)₂, NHCOCOOH), or the group-Y—(CH₂)_(n)-Z, where Y is O or S, nis 1, 2, or 3, and Z is hydrogen, methyl, branched alkyl (C3-C5),cycloalkyl (C3-C6), phenyl (unsubstituted or substituted with one ormore of the following: halogen, trifluoroalkyl, carboxy, alkoxycarbonyl(C1-C4), CF₂P═O(OH)₂, NHCOCOOH, or carboxyl; or (2) a pyridylthio groupeither unsubstituted or substituted with one or more halogen and/or oneor more nitro groups, methylenedioxyphenyl,benzo[3,4-c]1,2,5-oxadiazol-5-yl, 4-oxo-3-hydroquinazolin-2-yl, or agroup having formula (III) as follows:

in which the imidazole ring is unsubstituted or substituted with one ormore halogens.
 14. A pharmaceutical composition as recited in claim 11wherein R1 and R2 are taken together with the core unit to which theyare attached (formula I) to form a heterocyclic group having formula(IV) as follows:

wherein R6 and R7 are each independently as defined for R1, R2 and R3.15. A pharmaceutical composition as recited in claim 11 wherein R1 andR2 are linked through an aromatic ring, and taken together with theN═CR3—S unit to which they are attached, form a tricyclic heterocyclicgroup having formula (V) as follows:

Where R9, R10 and R11 are each independently as defined for R1, R2 andR3.
 16. A pharmaceutical composition as recited in claim 11 wherein R1and R2, taken together with the N═CR3—S unit to which they are attached,form a heterocyclic group having formula (VI) as follows:

Wherein R12 and R13 are each independently as defined for R1, R2 and R3.17. A pharmaceutical composition as recited in claim 11 wherein R1 andR3, taken together with the N═C—SR2 unit to which they are attached,form a heterocyclic group having formula (VII) as follows:

Wherein R14 and R15 are each independently as defined for R1, R2 and R3.18. A pharmaceutical composition as recited in claim 11 wherein R1 andR3, taken together with the N═C—SR2 unit to which they are attached,form a bicylic heterocyclic group having formula (VIII) as follows:

Wherein R18 and R19 are each independently as defined for R1, R2 and R3.19. A pharmaceutical composition as recited in claim 11 wherein R1, R2and R3, taken together with the N═C—S unit to which they are attached,form a bicyclic heterocyclic group having formula (IX) as follows:

Wherein R20, R21 and R22 are each independently as defined for R1, R2and R3.
 20. A pharmaceutical composition as recited in claim 11 whereinR1, R2 and R3, taken together with the N═C—S unit to which they areattached, form a bicyclic heterocyclic group having formula (X) asfollows:

Where R23 and R24 are each independently as defined for R1, R2 and R3.StructureNameTable Molecular Structure Molecular Name

N-(4-biphenyl-4-yl-thiazol-2-yl)-4-bromo-benz- amide

N2-(4-fluorophenyl)-5-(2-chlorophenyl)-1,3,4- thiadiazol-2-amine

N2-(3,4-dichlorophenyl)-5-(3-nitrophenyl)-1,3,4- thiadiazol-2-amine

2-[[5-(4-fluoroanilino)-1,3,4-thiadiazol-2-yl]thio]-1-(2-naphthyl)ethan-1-one

2-(4-chlorophenyl)-6-[3-(trifluoromethyl)phenyl]-7aH-azolidino[3,4-e]1,3-thiazine-5,7-dione

4-chloro-N-[6-phenyl-5-(trifluoromethyl)thieno[3,2-d][1,3]thiazol-2-yl]benzamide

N-[2-(4-chlorophenyl)-6-methyl(1,3-thiazolino[3,2-d]1,2,4-triazol-5-yl)](phenylamino)carboxamide

3,6-di(4-chlorophenyl)[1,2,4]triazol[3,4-b][1,3,4]thiadiazole

2-{4-amino-5-[(2,4-dimethylphenyl)carbonyl]thiopheno[3,2-d]isothiazol-3-ylthio}-1-(2,4-dimethylphenyl)ethan-1-one

[(2,4-dichlorophenyl)amino]-N-[2-(4-chloro-phenyl)-6-methyl(1,3-thiazolino[3,2-d]1,2,4-triazol-5-yl)]carboxamide

[2-(2,4-dichlorophenyl)hydrazino]-N-[2-(4-chloro-phenyl)-6-methyl(1,3-thiazolino[3,2-d]1,2,4-triazol-5-yl)]carboxamide

4-=[2-(4-chlorophenyl)[1,3]thiazolo[3,2-B][1,2,4]triazol-6-yl]benzene-1,3-diol

2-{5-[(2,6-dichlorophenyl)methylthio](1,3,4-thiadiazol-2-ylthio)}-5-bromo-3-nitropyridine

(2-anilino-1,3-thiazol-5-yl)(phenyl)methanone

(2-anilino-1,3-thiazol-5-yl)(4-bromo- phenyl)methanone

(2-anilino-1,3-thiazol-5-yl)(3,4-dichloro- phenyl)methanone

ethyl 2-[2-(3,4-dichloroanilino)-1,3-thiazol- 4-yl]benzenecarboxylate

[2-(4-chlorophenyl)-1,3-thiazol-5-yl](3,4- dichlorophenyl)methanone

6-(4-chlorophenyl)-2-phenylimidazolo[2,1- b]1,3,4-thiadiazoline

6-(4-bromophenyl)-2-phenylimidazolo[2,1- b]1,3,4-thiadiazoline

1-(4-nitrophenyl)-2-[5-(4-pentylphenyl)(4H-1,2,4-triazol-3-ylthio)]ethan-1-one

2,4-difluorophenylthio 2-(4-chlorophenyl)-6-methyl(1,3-thiazolino[3,2-d]1,2,4-triazol-5-yl) ketone

N2-(4-bromo-3-methylphenyl)-5-(2-phenoxy-3-pyridyl)-1,3,4-thiadiazol-2-amine

N-(3,4-dichlorophenyl)-2-(2,4-diphenyl-1,3- thiazol-5-yl)acetamide

2,4-difluorophenylthio 2-(4-chlorophenyl)-6-methyl(1,3-thiazolino[3,2-d]1,2,4-5-yl) ketone

N2-(2,4,5-trichlorophenyl)-8h-indeno[1,2-d][1,3]thiazol-2-aminhydrobromide

(3,5-dichlorophenyl)[5-(4-chlorophenyl)(1,3- thiazol-2-yl)]amine

N2-(2,4,5-trichlorophenyl)-4-(3-nitrophenyl)-1,3- thiazol-2-amine

(5-(2H,3H,4H-benzo[3,4-b]1,4-dioxepin-7-yl)(1,3-thiazol-2-yl))[3,5-bis(trifluoromethyl)phenyl]amine

N-(4-[1,1′-biphenyl]-4-yl-1,3-thiazol-2-yl)- 5-chloro-2-hydroxybenzamide

N1-[4-(2-naphthyl)-1,3-thiazol-2-yl]-5-bromo-2- hydroxybenzamide

N-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-3- pyridylcarboxamide

3-{2-[aza(4-bromo-3-chlorophenyl)methylene]-3-benzyl(1,3,4-thiadiazolin-5-yl)}-1-phenoxybenzene

(4-bromo-3-chlorophenyl)benzyl[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

2-{5-[(4-benzo-3-chlorophenyl)amino]-1,3,4-thiadiazol-2-yl}-3-hydroquinazolin-4-one

(5-benzo[3,4-c]1,2,5-oxadiazol-5-yl(1,3,4-thiadiazol-2-yl))(4-bromo-3-chlorophenyl)amine

(3-bromophenyl)[5-(3-{[3-(trifluoromethyl)-phenyl]methoxy}phenyl)(1,3,4-thiadiazol-2-yl)]amine

ethyl 4-{[5-(4-phenoxyphenyl)-1,3,4-thiadiazol-2- yl]amino}benzoate

(3,4-dichlorophenyl)[5-(3-{[4-(tert-butyl)phenyl]methoxy}phenyl)(1,3,4-thiadiazol-2-yl)]{[4-(tertbutyl)phenyl]methyl}amine

methyl-3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)benzoate

3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxcy)benzoic acid

5-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}-3-[3-(trifluoromethyl)phenoxy] phenol

(3,4-dichlorophenyl){5-[3-(3-nitrophenoxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

2-[3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]acetic acid

4-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenol

(3,4-dichlorophenyl)[5-(3-{[3-(trifluoro-methoxy)phenyl]methoxy}phenyl)(1,3,4-thiadiazol-2-yl)]amine

2-[4-(phenylmethoxy)phenyl]-N-(5-{3-[3-(tri-fluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))acetamide

naphthyl-N-(5-{3-[3-(trifluoromethyl)phenoxy]-phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

3-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methylthio]propanoicacid

ethyl 2-[(3-{5-[(3,4-dichlorophenyl)amino]-(1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]meethoxy]acetate

2-[(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methoxy]acetic acid

2-[4-(tert-butyl)phenoxy]-N-(5-{3-[3-(tri-fluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))acetamide

[2-(4-methoxyphenoxy)-5-nitrophenyl]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

[5-(3,5-dichlorophenoxy)(2-furyl)]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

(3-nitrophenyl)-N-(5-{3-[3-(trifluoromethyl)phen-oxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

meethyl 3-(azaq{5-(3-ethoxyphenyl)-3-[(4-phenyl-phenyl)methyl]*1,3,4-thiazolidin-2-ylidene)}methyl)benzoate

3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thia-diazol-2-yl}phenoxy)benzenecarbonitrile

3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thia-diazol-2-yl}phenoxy)benzenecarbonitrile

{5-[3-(3-(1H-1,2,3,4-tetrazol-5-yl)phenoxy)phenyl]-(1,3,4-thiadiazol-2-yl)}(3,4-dichlorophenyl)amine

[3-(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thia-diazol-2-yl)}phenoxy)phenyl]-N-(1,3-dioxolan-2-ylmethyl)carboxamide

3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thiadiazol- 2-yl)}phenyl3-(trifluoromethyl)phenyl ketone

(3-bromophenyl)[2-(3-nitrophenyl)(1,3-thiazol-5- yl)]amine

N-(3-{5-[(3-bromophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)-4-methylpentanamide

[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)][4-(3-methylbutylthio)phenyl]amine

(3-{5-[(3-bromophenyl)aqmino](1,3,4-thiadiazol-2-yl)}phenyl)(naphthylsulfonyl)amine

3-{2-[aza(3,4-dichlorophenyl)methylene]-3-methyl(1,3,4-thiadiazolin-5-yl)}-1-[3-(trifluoromethyl)phenoxy]benzene

(3,4-dichlorophenyl)methyl(5-{3-[3-(trifluoro-methyl)phenopxy]phenyl}(1,3,4-thiadiazol-2-yl))amine

3-methoxy-1-[6-(4-phenylphenyl)imidazolo[2,1-b]1,3,4-thiadiazolin-2-yl]benzene

1-{6-[3-(2,4-dichlorophenyl)isoxazol-5-yl]-imidazolo[2,1-b]1,3,4-thiadiazoln-2-yl}-3-methoxybenzene

2-(3-nitrophenyl)-6-(4-phenylphenyl)imidazolo[2,1- b]1,3,4-thiadiazoline

6-(2H,3H,4H-benzo[b]1,4-dioxepan-7-yl)-2-(3-nitro-phenyl)imidazolo[2,1-b]1,3,4-thiadiazoline

{3-[(4-methoxyphenyl)methylthio]phenyl}[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

[5-(3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)]{3-[(4-phenylphenyl)methylthio]phenyl}amine

[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]{3-[(4-phenylphenyl)methylthio]phenyl}amine

[5-(3-nitrophenyl;)(1,3,4-thiadiazol-2-yl)]{3-[(4-phenylphenyl)methylthio]phenyl}amine

3-[3-(3-{5-[(3,4-dichlorophenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)phenyl]propanoic acid

{5-[3,5-bis(phenylmethoxy)phenyl](1,3,4-thia-diazol-2-yl)}[3-(3-phenylpropylthio)phenyl]amine

{5-[3,5-bis(phenylmethoxy)phenyl](1,3,4-thia-diazol-2-yl)}{3-[(2-phenylphenyl)methylthio]phenyl}amine

{3-[(2-phenylphenyl)methylthio]phenyl}{5-[2-(trifluoromethyl)phenyl](1,3,4-thiadiazol-2-yl)}amine

[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)][3-(3-phenylpropylthio)phenyl]amine

3-{4-[5-({3-[(2-phenylphenyl)methylthio]-phenyl}amino)(1,3,4-thiadiazol-2-yl)]phenyl}prop-2-enoic acid

4-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thia-diazol-2-yl}amino)benzoic acid

2-{4-[3-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)phenoxy]phenyl}acetic acid

(3-bromophen yl)[5-(3-nitrophenyl)(1,3-thiazol-2- yl)]amine

methyl 4-{[(3,4-dichlorophenyl)(5-{3-[3-(tri-fluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amino]methyl}benzoate

4-{[(3,4-dichlorophenyl)(5-{3-[3-(trifluoro-methyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amino]methyl}benzoic acid

(3,4-dichlorophenyl)(5-{3-[3-(oxymethyl)phenoxy]-phenyl}(1,3,4-thiadiazol-2-yl))amine

1-(4-{[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]-amino}phenyl)ethan-1-one

ethyl 2-(3-{5-[(3-bromophenyl)amino]-1,3,4-thia-diazol-2-yl}phenoxy)acetate

[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-phenoxy- phenyl)amine

(4-bromo-3-chlorophenyl)[5-(4-ethoxyphenyl)(1,3,4-thia-diazol-2-yl)]amine

(3-bromophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol- 2-yl)]benzylamine

2-[aza-(3-bromophenyl)methylene]-5-(3-nitro-phenyl)-3-benzyl-1,3,4-thiadiazoline

[5-(3,4-dimethoxyphenyl)(1,3,4-thiadiazol-2-yl)](4-bromo-3-chlorophenyl)amine

4-{5-[(4-bromo-3-chlorophenyl)amino]-1,3,4-thiadiazol-2-yl}benzene-1,2-diol

(4-bromo-3-chlorophenyl)[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

(4-{5-[(4-bromo-3-chlorophenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)diethylamine

(4-bromo-3-chlorophenyl)[5-(3-0methylphenyl)(1,3,4-thiadiazol-2-yl)]amine

(naphthylmethyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol- 2-yl)]amine

(3,4-dichlorophenyl)[5-(4-phenylphenyl)(1,3,4-thia- diazol-2-yl)]amine

(4-{5-[(3,4-dichlorophenyl)amino](1,3,4-thia-diazol-2-yl)}phenyl)dimethyamine

(3,4-dichlorophenyl)[5-(4-methylthiophenyl)(1,3,4-thia-diazol-2-yl)]amine

methyl-3-({2-[aza(3,4-dichlorophenyl)methylene]--(3-ethoxyphenyl)-1,m3,4-thiadiazol-3-yl}methyl)benzoate

(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thia-diazol-2-yl)][(4-phenylphenyl)methyl]amineethyl)benzoate

(3,4-dichlorophenyl){[4-(tert-butyl)phenyl]-methyl}[5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)]amine

1-({2-[aza(3,4-dichlorophenyl)methylene]-5-(3-ethoxyphenyl)(1,3,4-thiadiazolin-3-yl)}methyl)-3-methoxybenzene

(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thia-diazol-2-yl)][(3-nitrophenyl)methyl]amine

3-{2-[aza(3,4-dichlorophenyl)methylene]-3-(2-naphthylmethyl)(1,3,4-thiadiazolin-5-yl)}-1-ethoxybenzene

(3,4-dichlorophenyl)[5-(3-ethoxyphenyl)(1,3,4-thia-diazol-2-yl)](2-naphthylmethyl)amine

(3,4-dichlorophenyl){5-[3-(4-methoxyphenoxy)-phenyl](1,3,4-thiadiazol-2-yl)}-amine

(3,4-dichlorophenyl){5-[3-(4-methylphenoxy)-phenyl](1,3,4-thiadiazol-2-yl)}amine

(3,4-dichlorophenyl){5-[3-(3,5-dichlorophenoxy)-phenyl](1,3,4-thiadiazol-2-yl)}amine

(3,4-dichlorophenyl){5-[3-(3,4-dichlorophenoxy)-phenyl](1,3,4-thiadiazol-2-yl)}amine

(3,4-dichlorophenyl)(5-{3-[3-(trifluoromethyl)-phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))amine

(5-(2H-benzo[d]1,3-dioxolan-5-yl)(1,3,4-thia-diazol-2-yl))(3,4-dichlorophenyl)amine

[(4-{[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl]amino}phenyl)sulfonyl]piperidine

(4-bromo-3-chlorophenyl)[5-(3-nitrophenyl)(1,3,4- thiadiazol-2-yl)]amine

[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]-(2,3,4,5-tetrachlorophenyl)amine

(3-chloro-4-methylphenyl)[5-(3-nitrophenyl)-(1,3,4-thiadiazol-2-yl)]amine

(4-methylphenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

[4-(methylethyl)phenyl][5-(3-nitrophenyl)- (1,3,4-thiadiazol-2-yl)]amine

(4-butylphenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

(4-decylphenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]-[4-(4-nitrophenoxy)phenyl]amine

(3-methylphenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

[(4-{[5-(3-methoxyphenyl)-1,3,4-thiadia-zol-2-yl]amino}phenyl)sulfonyl]piperidine

[(4-{[5-(3-methylphenyl)-1,3,4-thiadia-zol-2-yl]amino}phenyl)sulfonyl]piperidine

(5-chloro-2,4-dimethoxyphenyl)[5-(3-nitro-phenyl)(1,3,4-thiadiazol-2-yl)]amine

(3-chloro-4-methylphenyl){5-[3-(phenylmeth-oxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

(3-chloro-4-methylphenyl)[5-(4-morpholin-4-yl-3-nitrophenyl)(1,3,4-thiadiazol-2-yl)]amine

2-(3-{5-[(3-chloro-4-methylphenyl)amino]-1,3,4-thiadiazol-2-yl}phenoxy)ethan-1-ol

(3-chloro-4-methylphenyl){5-[4-(trifluoro-methylthio)phenyl](1,3,4-thiadiazol-2-yl)}amine

[(4-{[5-(4-bromo-3-chlorophenyl)-1,3,4-thia-diazol-2-yl]amino}phenyl)sulfonyl]piperidine

[(4-{[5-(3-bromo-4-chlorophenyl)-1,3,4-thia-diazol-2-yl]amino}phenyl)sulfonyl]piperidine

(3-chloro-4-methylphenyl){5-[3-(trifluorometh-oxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

(5-{3-[4-(tert-butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(3-chloro-4-methylphenyl)amine

(3,4-dichlorophenyl){5-[4-methoxy-3-(phenylmeth-oxy)phenyl](1,3,4-thiadiazol-2-yl)}amine

(3,4-dichlorophenyl){5-[4-(trifluoromethoxy)-phenyl](1,3,4-thiadiazol-2-yl)}amine

(3,4-dichlorophenyl)[5-(4-butoxyphenyl)(1,3,4-thia- diazol-2-yl)]amine

2-(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thia-diazol-2-yl)}phenoxy)-1-(4-methylpiperidyl)ethan-1-one

(5-{3-[4-(tert-butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))indan-2-ylamine

(5-{3-[4-(tert-butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(3,3,5-trimethylcyclohexyl)amine

(5-{3-[4-(tert-butyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))(methylhexyl)amine

(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}-(1,3,4-thiadiazol-2-yl))(3,3,5-trimethylcyclohexyl)amine

(4-bromo-3-chlorophenyl)[5-(3-phenoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

(3-bromophenyl)[5-(2-nitrophenyl)(1,3-thiazol-2- yl)]amine

(3-bromophenyl)[4-(4-chloro-3-meethylphenyl)(1,3- thiazol-2-yl)]amine

(3-bromophenyl)[4-(3-methoxyphenyl)(1,3-thiazol- 2-yl)]amine

(4-{2-[(3,4-dichlorophenyl)amino](1,3-thia-zol-4-yl)}phenyl)diethylamine

N-{2-aza-2-(3-bromophenyl)-1-[(4-phenylphenyl)-methylthio]vinyl}[3-(trifluoromethyl)phenyl]carboxamide

(2Z)-2-aza-3-[(3,4-dichlorophenyl)amino]-1-(3-methoxyphenyl)-3-{[3-(trifluoromethylthio)phenyl]methylthio}prop-2-en-1-one

(3,4-dichlorophenyl)[4-(4-pyrrolidinylphenyl)(1,3- thiazol-2-yl)]amine

4-{2-[(3,4-dichlorophenyl)amino]-1,3-thiazol- 4-yl}benzenecarbonitrile

(3-bromophenyl)[4-(3-chloro-4-methylphenyl)-5-methyl(1,3-thiazol-2-yl)]amine

(3-bromophenyl)[4-(4-methylphenyl)(1,3-thiazol- 2-yl)]amine

3-{2-[(3-bromophenyl)amino]-1,3-thiazol-4- yl}phenyl benzoate

4-{2-[(3-bromophenyl)amino]-1,3-thiazol-4- yl}phenyl benzoate

[3-(trifluoromethyl)phenyl]-N-(5-{3-[3-(trifluoromethyl)phenoxy]phenyl}(1,3,4-thiadiazol-2-yl))carboxamide

N-{2-aza-2-(3,4-dichlorophenyl)-1-[(4-(1,2,3-thiadiazol-4-yl)phenyl)methylthio]vinyl}[3-(trifluoromethyl)phenyl]carboxamide

N-{2-aza-2-(3,4-dichlorophenyl)-1-[(4-phenyl-phenyl)methylthio]vinyl}[3-(trifluoromethyl)phenyl]carboxamide

N-{2-aza-2-(3-bromophenyl)-1-[(4-(1,2,3-thia-diazol-4-yl)phenyl)methylthio]vinyl}[3-(trifluoromethyl)phenyl}carboxamide

(3-{5-[(3,4-dichlorophenyl)amino](1,3,4-thia-diazol-2-yl)}phenyl)[3-(trifluoromethyl)phenyl]methan-1-ol

(3,4-dichlorophenyl)[5-(3-(ethoxy[3-(trifluoro-methyl)phenyl]methyl}phenyl)(1,3,4-thiadiazol-2-yl)]amine

3-{5-[(3-bromophenyl)amino]-1,3,4-thiadiazol- -yl}benzoic acid

(3-nitrophenyl)[5-(3-nitrophenyl)(1,3,4-thiadiazol- 2-yl)]amine

(2-chloro-5-nitrophenyl)[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amine

[5-(3-methoxyphenyl)(1,3,4-thiadiazol-2-yl)](3- nitrophenyl)amine

[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)](3- nitrophenyl)amine

[5-(3-methylphenyl)(1,3,4-thiadiazol-2-yl)](3- nitrophenyl)amine

Deleted Entry

[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)][3-(trifluoromethyl)phenyl]amine

(3-methoxyphenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

(4-nitrophenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

(4-ethylphenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

(3,4-dichlorophenyl){5-[3,5-bis(phenyl-methoxy)phenyl](1,3,4-thiadiazol-2-yl)}-amine

[3-(phenylmethoxy)phenyl](5-{3-[3-(tri-fluoromethyl)phenoxy]phenyl}(1,3,4-thidiazol-2-yl))amine

(5-benzo[c]1,2,5-oxadiazol-5-yl(1,3,4-thia-diazol-2-yl))(3,4-dichlorophenyl)amine

(5-benzo[3,4-c]1,2,5-oxadiazol-5-yl(1,3,4-thia-diazol-2-yl))(2,3-dichlorophenyl)amine

[5-({2-[(4,5-dichloroimidazolyl)methyl]phen-oxy}methyl)(1,3,4-thiadiazol-2-yl)](4-bromo-3-chlorophenyl)amine

Deleted Entry

(4-{[5-(3-ethoxyphenyl)(1,3,4-thiadiazol-2-yl)]amino}phenyl)(phenylsulfonyl)amine

[(4-methylphenyl)sulfonyl](4-{[5-(3-nitrophenyl)(1,3,4-thiadiazol-2-yl)amino}phenyl)amine

(3,4-dibromophenyl)[5-(3,5-dimethoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(2,3-dichlorophenyl)[5-(3-nitrophenyl)(1,3,4- thiadiazol-2-yl)]amine

methyl 3-{[5-(3-nitrophenyl)-1,3,4-thia- diazol-2-yl]amino}benzoate

(3-bromophenyl)[5-(3-ethoxyphenyl)(1,3,4-thia- diazol-2-yl)]amine

(4-bromo-3-chlorophenyl)[5-(3-methoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(3-chloro-4-fluorophenyl)[5-(3-ethoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(4-bromo-3-methylphenyl)[5-(3-ethoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(4-bromo-3-methylphenyl)[5-(3-methoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(4-bromo-3-methylphenyl)[5-(3-nitrophenyl)-(1,3,4-thiadiazol-2-yl)]amine

(3-chloro-4-fluorophenyl)[5-(3-methoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(3-chloro-4-fluorophenyl)[5-(3-nitrophenyl)-(1,3,4-thiadiazol-2-yl)]amine

Deleted Entry

(4-bromo-3-chlorophenyl)[5-(3-ethoxyphenyl)-(1,3,4-thiadiazol-2-yl)]amine

(4-bromophenyl)[5-(3-nitrophenytl)(1,3,4-thia- diazol-2-yl)]amine

(2,5-dibromophenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

(3-bromophenyl)[5-(3-methoxyphenyl)(1,3,4-thia- diazol-2-yl)]amine

(3-bromophenyl)[5-(3-nitrophenyl)(1,3,4-thia- diazol-2-yl)]amine

ammonium 3-{4-[5-({3-[(2-phenylphenyl)-methylthio]phenyl}amino)(1,3,4-thiadiazol-2-yl)]phenyl}prop-2-enoate

ethyl 2-[(1Z)-1-aza-2-(3-{5-[(3,4-dichloro-phenyl)amino](1,3,4-thiadiazol-2-yl)}phenyl)-2-[3-(trifluoromethyl)phenyl]vinyloxy]acetate

3-({5-[3,5-bis(phenylmethoxy)phenyl]-1,3,4-thiadiazol-2-yl}amino)benzoic acid

(1-(2-[aza(3,4-dichlorophenyl)methylene]-3-{[4-(tert-butyl)phenyl]methyl}(1,3,4-thiadiazolin-5-yl))-3-ethoxybenzene)

Structure Name Compound #

3-{3-[5-(3,4-Dichloro- phenylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2- yl]-phenoxy}-benzoic acid 164

4-{N′-[1-(3-{5-[3-(3- Trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-2- ylamino}-phenyl)-ethylidene]-hydrazino}-benzoic acid 165

4-{[5-(3-Phenoxy-phenyl)- [1,3,4]thiadiazol-2-ylamino]- methyl}-benzoicacid 166

3,4[thiadiazol-2-yl]-amino}- methyl)-phenyl]-oxalamicacid 167

4-{[(4-Biphenyl-4-yl-thiazol- 2-yl)-(3,4-dichloro-phenyl)-amino]-methyl}-benzoic acid 168

N-{4-[((3,4-Dichloro-phenyl)- {5-[3-(3-trifluoromethyl-phenoxy)-phenyl]- [1,3,4]thiadiazol-2yl}-amino)-methyl]-phenyl}-oxalamic acid 169

(4-{2-(3,4-Dichloro- phenylimino)-5-[3-(3- trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-3-yl- methyl}-phenyl)- acetic acid 170

4-[5-(3-{3-[5-(3,4-Dichloro- phenylamino)- [1,3,4]thiadiazol-2-yl]-phenoxy}-phenyl)-tetrazol-1- yl]-butyric acid 171

4-[N′-(3-{3-[5-(3,4-Dichloro- phenylamino)- [1,3,4]thiadiazol-2-yl]-phenoxy}-benzylidene)- hydrazino]-benzoic acid 172

7-(3-{3-[5-(3,4-Dichloro- phenylamino)- [1,3,4]thiadiazol-2yl]-phenoxy}-phenyl)-hept- 6-enoic acid 173

4-[2-(3,4-Dichloro- phenylimino)-5-(4-phenoxy-phenyl)-[1,3,4]thiadiazol-3- ylmethyl]-benzoic acid. 174

[4-(Piperidine-1-sulfonyl)- phenyl]-[4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-amine 175

4-({(3,4-Dichloro-phenyl)- [4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-amino}-methyl)- benzoic acid 176

4-{3-[5-((3-(3- Hydroxycarbonylbenzyl)-5- Benzyloxy-phenyl)-[1,3,4]thiadiazol-2-ylamino]- phenylsulfanylmethyl}- benzoic acid 177

4-[4-(4-hydroxycarbonyl- benzyl)-5-(3,4-dichloro-phenylimino)-4,5-dihydro- [1,3,4]thiadiazol-2-yl]benzoic acid 178

4-({(4-Hydroxycarbonyl- benzyl-[5-(3-phenoxy- phenyl)-[1,3,4]thiadiazol-2-yl]-amino}-methyl)- benzoic acid 179

4-[2-(3-Bromo-phenylimino)- 5-(3-nitro-phenyl)-[1,3,4]thiadiazol-3-ylmethyl]- benzoic acid 180

3-(3-{5-[(4-Hydroxycarbonyl- benzyl)-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2- yl}-phenoxy)-benzoic acid 181

{2-(3,4-Dichloro- phenylimino)-5-[3-(3- trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-3- yl}-acetic acid 182

((3,4-Dichloro-phenyl)-{5- [3-(3-tifluoromethyl- phenoxy)-phenyl]-[1,3,4]thiadiazol-2-yl}- amino)-acetic acid 183

4-[2-(3,4-Dichloro- phenylimino)-5-(3-phenoxy-phenyl)-[1,3,4]thiadiazol-3- ylmethyl]-benzoic acid 184

4-[2-Isopropylimino-5-(3- phenoxy-phenyl)-[1,3,4]thiadiazol-3-ylmethyl]- benzoic acid 185

4-{5-(3-Ethoxy-phenyl)-2-[4- (piperidine-1-sulfonyl)- phenylimino]-[1,3,4]thiadiazol-3-ylmethyl}- benzoic acid 186

4-{2-(3,4-Dichloro- phenylimino)-5-[3{3- trifluoromethyl-phenoxy)-phenyl]-[1,3,4]thiadiaziol-3- ylmethyl}-benzoic acid 187

3-[5-(3,5-Bis-benzyloxy- phenyl)-[1,3,4]thiadiazol-2- ylamino]-benzoicacid 188

3-[5-(3,5-Bis-benzyloxy- phenyl)-[1,3,4]thiadiazol-2- ylamino]-phenol189

[1-(3-{5-[3-(3- Trifluoromethyl-phenoxy)- phenyl]-[1,3,4]thiadiazol-2-ylamino}-phenyl)- ethylideneaminooxy]acetic acid 190

4-[N′-(3-{3-[5-(3,4-Dichloro- phenylimino-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2- yl]-phenoxy}-benzylidene)-hydrazino]-benzoic acid 191

4-{N′[3-{5-[(3,4-Dichloro- phenyl)-methyl-amino)-[1,3,4]thiadiazol-2-yl}- phenoxy)-benzylidene[- hydrazino}-benzoic acid192

5-[5-(3-{3-[5-(3,4-Dichoro- phenylamino)- [1,3,4]thiadiazol-2-yl]-phenoxy}-phenyl)-tetrazol-1- yl]-pentanoic acid 193

4-{N′-[{3-[5-(3,4-Dichloro- phenylamino)- [1,3,4]thiadiazol2-yl]-phenyl}-(3-trifluoromethyl- phenyl)-methylene]- hydrazino}-benzoic acid194

3-(3-Benzyloxy-5-{5-[3-(5- carboxy-pentylsulfanyl)- phenylamino]-[1,3,4]thiadiazol-2-yl}- phenoxymethyl)-benzoic acid 195

{3-[5-(3,4-Dichloro- phenylamino)- [1,3,4]thiadiazol-2-yl]-phenyl}-(3-trifluoromethyl- phenyl)-methylsulfanyl]- acetic acid 196

3-{5-[3,5-Bis-(3-methoxy- phenoxy)-phenyl]- [1,3,4]thiadiazol-2-ylamino}-benzoic acid 197

3-{5-[3,5-Bis-(3- trifluoromethyl-phenoxy)- phenyl]-[1,3,4]thiadiazol-2-ylamino}-benzoic acid 198

[2-(3-{3-[5-(3,4-Dichloro- phenylamino)- [1,3,4]thiadiazol-2-yl]-phenoxy}-phenyl)-1,1- difluoro-2-hydroxy-ethyl]- phosphonic acid 199

{5-[2-(4-Bromo-3-chloro- phenylimino)-5-(3-ethoxy-phenyl)-[1,3,4]thiadiazol-3- yl]-1,1-difluoro-pentyl}- phosphonic acid200

[(4-{3-[5-(3,4-Dichloro- phenylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2- yl]-phenoxy}-phenyl)- difluoro-methyl]-phosphonic acid 201

{[4-({(3,4-Dichloro- phenyl)-[5-(3-phenoxy- phenyl)-[1,3,4]thiadiazol-2-yl]-amino}-methyl)-phenyl]- difluoro-methyl}- phosphonic acid 202

({4-[2-(3,4-Dichloro- phenylimino)-5-(3-phenoxy-phenyl)-[1,3,4]thiadiazol-3- ylmethyl]-phenyl}-difluoro-methyl)-phosphonic acid 203

4-({[4-(Difluoro-phosphono- methyl)-benzyl]-[5-(3- phenoxy-phenyl)-[1,3,4]thiadiazol-2-yl]- amino}-methyl)-benzoic acid 204